ES2284587T3 - 1,5-BENZOTIAZEPINAS AND ITS USE AS ANTIHIPERLIPIDEMICOS. - Google Patents

Abstract

A compound of ** formula **, in which: Rv and Rw are independently selected from hydrogen or C1-6 alkyl; R1 and R2 are independently selected from C1-6 alkyl; RX and RY are independently selected from hydrogen or C1-6 alkyl, or one of RX and RY is hydrogen or C1-6 alkyl and the other is hydroxy or C1-6 alkoxy; Rz is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkanoyl, C1- alkanoyl 6-oxy, N- (C1-6 alkyl) amino, N, N- (C1-6 alkyl) 2amino, C1-6 alkanoyl, N- (C1-6 alkyl) -carbamoyl, N, N- (alkyl C1-6) 2carbamoyl, C1-6-S alkyl (O) a in which a is 0 to 2, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonylamino, ureido, N '' - (C1-6 alkyl ) ureido, N- (C1-6 alkyl) ureido, N '', N- (C1-6 alkyl) 2ureido, N '' - (C1-6 alkyl) -N- (C1-6 alkyl) ureido, N ' ', N' '- (C1-6 alkyl) 2-N- (C1-6 alkyl) ureido, N- (C1-6 alkyl) sulfamoyl and N, N- (C1-6 alkyl) 2sulfamoyl; v is 0-5.

Description

1,5-benzothiazepines and their use as antihyperlipidemic.

This invention relates to derivatives benzothiazepines, or pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof. The Prodrugs of this invention are esters or hydrolyzable amides. These benzothiazepines have a transport inhibitory activity of bile acids present in the ileum (IBAT), and consequently have a value in the treatment of diseases associated with hyperlipidemic pathologies, and are useful in treatment methods of a warm-blooded animal, just like man. The invention also refers to procedures for the manufacture of said benzothiazepine derivatives, to pharmaceutical compositions that contain, and for use in the manufacture of drugs to inhibit IBAT in a warm-blooded animal, such as man.

It is well known that hyperlipidemic states associated with high concentrations of total cholesterol and low-density lipoprotein cholesterol are important risk factors for cardiovascular atherosclerotic disease (for example, "Coronary Heart Disease: Reducing the Risk; a Worldwide View" Assman G ., Carmena R. Cullen P. et al ; Circulation 1999, 100, 1930-1938, and "Diabetes and Cardiovascular Disease: A Statement for Healthcare Professionals from the American Heart Association" Grundy S, Benjamin L, Burke G., et al ; Circulation, 1999, 100, 1134-46). It is found that interference with the circulation of bile acids within the lumen of the intestinal tubes reduces the level of cholesterol. Consolidated prior therapies, to reduce cholesterol concentration, involve, for example, treatment with HMG CoA reductase inhibitors, preferably statins such as simvastatin and fluvastatin, or treatment with bile acid binders, such as resins. For example, frequently used bile acid binders are cholestyramine and colestipol. A recently proposed therapy ("Bile Acids and Lipoprotein Metabolism: a Renaissance for Bile Acids in the Post Statin Era" Angelin B, Eriksson M, Rudling M; Current Opinion on Lipidology, 1999, 10, 269-74) involves substance treatment with an inhibitory effect of IBAT.

Bile acid reabsorption from the tube digestive is a normal physiological process that takes place mainly in the ileum, through the mechanism of IBAT. The IBAT inhibitors can be used in the treatment of hypercholesterolemia (see, for example, "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolaemic properties ", Biochemica et Biophysica Acta, 1210 (1994) 255-287). In this way, the compounds suitable that have such an IBAT inhibitory activity are also useful in the treatment of hyperlipidemic states. They have described compounds possessing such IBAT inhibitory activity; see, for example, the compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/38182, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68906 and EP 0 864 582.

A further aspect of this invention is refers to the use of the compounds of the invention in the treatment of dyslipidemic states and disorders such as hyperlipidemia, hypertriglyceridemia, hyperbetalipoproteinemia (elevated LDL), hyperprebetalipoproteinemia (elevated VLDL), hyperkylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia e hypoalphalipoproteinemia (low HDL). Also, hopefully these compounds are useful for the prevention and treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hypertrombotic states, dysfunction vascular, endothelial dysfunction, heart failure, coronary heart disease, cardiovascular disease, heart attack myocardium, angina pectoris, peripheral venous insufficiencies, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurysms, stenosis, restenosis, vascular plaques, vascular fatty streaks, infiltration of leukocytes, monocytes and / or macrophages, thickening of the intimate, thinning of the stocking, infectious and surgical trauma and vascular thrombosis, stroke and transient ischemic attacks.

The present invention is based on the discovery that certain benzothiazepine compounds inhibit surprisingly IBAT. Hopefully such properties are valuable in the treatment of diseases associated with states hyperlipidemic

Accordingly, the present invention provides a compound of formula (I):

one

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in the that:

R v and R w are selected, independently of hydrogen or alkyl C 1-6;

R 1 and R 2 are selected, independently, from C 1-6 alkyl;

quad

R X and R Y are selected, independently of hydrogen or alkyl C 1-6, or one of R X and R Y is hydrogen or C 1-6 alkyl and the other is hydroxy or alkoxy C 1-6;

quad

R z is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyl -oxy, N - (C 1-6 alkyl) amino, N, N - (C 1-6 alkyl ) 2-amino, C 1-6 alkanoyl-amino, N - (C 1-6 alkyl) -carbamoyl, N, N- (C 1-6 alkyl) 2 carbamoyl , C 1-6 alkyl-S (O) a in which a is 0 to 2, C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonylamino, ureido, N ' - (C 1-6 alkyl) ureido, N - (C 1-6 alkyl) ureido, N ', N' - (C 1-6 alkyl) 2 ureido, N '- ( C 1-6 alkyl) - N - (C 1-6 alkyl) ureido, N ', N' - (C 1-6 alkyl) 2 - N - (C 1- alkyl) 6) ureido, N - (C 1-6 alkyl) sulfamoyl and N, N - (C 1-6 alkyl) 2 sulfamoyl;

v is 0-5;

one of R 4 and R 5 is a group of formula (IA):

2

quad

R 3 and R 6 and the other of R 4 and R 5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, C 2-4 achenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyl - oxy, N - (C 1-4 alkyl) amino, N, N - (C 1-4 alkyl) 2 amino, C 1-4 alkanoyl -amino, N - (C_ alkyl 1-4) carbamoyl, N, N - (C 1-4 alkyl) 2 carbamoyl, C 1-4 alkyl -S (O) a in which a is 0 to 2 , C 1-4 alkoxycarbonyl, N - (C 1-4 alkyl) sulfamoyl and N, N - (C 1-4 alkyl) 2 sulfamoyl; wherein R 3 and R 6 and the other of R 4 and R 5 may be optionally substituted on the carbon with one or more R 16;

D is -O-, -N (R a) -, -S (O) b - or -CH (R a) -; in which R a is hydrogen or C 1-6 alkyl, and b is 0-2;

quad

ring A is aryl or heteroaryl; in which the ring A is optionally substituted with one or more substituents selected from R17;

quad

R 7 is hydrogen, alkyl C 1-4, carbocyclyl or heterocyclyl; in which R 7 is optionally substituted with one or more substituents selected from R18;

R 8 is hydrogen or alkyl C 1-4;

R 9 is hydrogen or alkyl C 1-4;

quad

R 10 is hydrogen, alkyl C 1-4, carbocyclyl or heterocyclyl; in which R 10 is optionally substituted with one or more substituents selected from R19;

quad

R 11 is carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P (O) (OR c) (OR d), -P (O) (OH) (OR c), -P (O) (OH) (R d) or -P (O) (OR c) (R d), in which R c and R d are independently selected from alkyl C 1-6; or R 11 is a group of formula (IB):

3

in the that:

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X is -N (R q) -, -N (R q) C (O) -, -O-, and -S (O) a -; where a is 0-2 and R q is hydrogen or C 1-4 alkyl;

R 12 is hydrogen or alkyl C 1-4;

quad

R 13 and R 14 are selected, independently, of hydrogen, C 1-4 alkyl, carbocyclyl, heterocyclyl or R23; in which said alkyl C 1-4, carbocyclyl or heterocyclyl may be optionally substituted, independently, with one or more substituents selected from R20;

quad

R 15 is carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P (O) (OR e) (OR f), -P (O) (OH) (OR e), -P (O) (OH) (R e) or -P (O) (OR e) (R f), in which R e and R f are independently selected from alkyl C 1-6; or R 15 is a group of formula (IC):

4

in the that:

R 24 is selected from hydrogen or alkyl C 1-4;

quad

R 25 is selected from hydrogen, alkyl C 1-4, carbocyclyl, heterocyclyl or R 27; wherein said C 1-4 alkyl, carbocyclyl or heterocyclyl may be optionally substituted, so independent, with one or more substituents selected from R 28;

quad

R 26 is selected from carboxy, sulfo, sulfine, phosphono, tetrazolyl, -P (O) (OR g) (OR h), -P (O) (OH) (OR g), -P (O) (OH) (R g) or -P (O) (OR g) (R h), in which R g and R h are independently select from alkyl C 1-6;

p is 1-3; in which the values of R 13 may be the same or different;

q is 0-1;

r is 0-3; in which the values of R 14 may be the same or different;

m is 0-2; in which the values of R 10 may be the same or different;

n is 1-3; in which the values of R 7 may be the same or different;

z is 0-3; in which the values of R 25 may be the same or different;

quad

R 16, R 17 and R 18 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, alkenyl C 2-4, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyl -oxy, N - (C 1-4 alkyl }) amino, N, N - (C 1-4 alkyl) 2 amino, C 1-4 alkanoyl -amino, N- (C 1-4 alkyl) carbamoyl, N, N - (C 1-4 alkyl) 2 carbarnoyl, C 1-4 alkyl -S (O) a in which a is 0 to 2, C 1-4 alkoxycarbonyl, N - (C 1-4 alkyl) sulfamoyl and N, N - (C 1-4 alkyl) 2 sulfamoyl; wherein R 16, R 17 and R 18 may be optionally independently substituted on the carbon with one or more R 21;

quad

R 19, R 20, R 23, R 27 and R 28 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto , sulfamoyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyl -oxy, N - (C 1-4 alkyl) amino, N, N - (C 1-4 alkyl) 2-amino, C 1-4 alkanoyl -amino, N - (alkyl C 1-4) carbamoyl, N, N - (C 1-4 alkyl) 2 carbamoyl, C 1-4 alkyl -S (O) a in which a is 0 a 2, C 1-4 alkoxycarbonyl, N - (C 1-4 alkyl) -sulfamoyl, N, N - (C 1-4 alkyl) 2 sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P (O) (OR a) (OR b), -P (O) (OH) (OR a), -P (O) ( OH) (R a) or -P (O) (OR a) (R b), in which R a and R b are independently selected from C 1-6 alkyl; wherein R 19, R 20, R 23, R 27 and R 28 may be optionally independently substituted on the carbon with one or more R 22;

quad

R21 and R22 are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy , vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N- methylcarbamoyl, N, N- dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N- methyl sulfamoyl and N, N- dimethyl ;

or a pharmaceutically salt acceptable, solvate, solvate of such salt or prodrug of same.

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According to an additional aspect of the present Invention, a compound of formula (I ') is provided:

5

in the that:

R 1 and R 2 are selected, independently, from C 1-6 alkyl;

one of R 4 and R 5 is a group of formula (IA '):

6

quad

R 3 and R 6 and the other of R 4 and R 5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyl - oxy, N - (C 1-4 alkyl) amino, N, N - (C 1-4 alkyl) 2 amino, C 1-4 alkanoyl -amino, N - (C_ alkyl 1-4) carbamoyl, N, N - (C 1-4 alkyl) 2 carbamoyl, C 1-4 alkyl -S (O) a in which a is 0 to 2 , C 1-4 alkoxycarbonyl, N - (C 1-4 alkyl) sulfamoyl and N, N - (C 1-4 alkyl) 2 sulfamoyl; wherein R 3 and R 6 and the other of R 4 and R 5 may be optionally substituted on the carbon with one or more R 12;

quad

ring A is aryl or heteroaryl; in which the ring A is optionally substituted with one or more substituents selected from R 13;

quad

R 7 is hydrogen, alkyl C 1-4, carbocyclyl or heterocyclyl; in which R 7 is optionally substituted with one or more substituents selected from R 14;

quad

R 8 is hydrogen, alkyl C 1-4, carbocyclyl or heterocyclyl; in which R 8 is optionally substituted with one or more substituents selected from R 15;

quad

R 9 is carboxy, sulfo, sulfino, phosphono, -P (O) (OR c) (OR d), -P (O) (OH) (OR c), -P (O) (OH) (R d) or -P (O) (OR c) (R d), in the that R c and R d are independently selected from alkyl C 1-6; or R 9 is a group of formula (IB '):

7

in the that:

quad

R 10 is hydrogen, alkyl C 1-4, carbocyclyl or heterocyclyl; in which R 10 is optionally substituted with one or more substituents selected from R 16;

quad

R 11 is carboxy, sulfo, sulfino, phosphono, -P (O) (OR e) (OR f), -P (O) (OH) (OR e), -P (O) (OH) (R e) or -P (O) (OR e) (R f), in the that R e and R f are independently selected from alkyl C 1-6;

p is 1-3; in which the values of R 10 may be the same or different;

m is 0-2; in which the values of R 8 may be the same or different;

n is 1-3; in which the values of R 7 may be the same or different;

quad

R 12, R 13 and R 14 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, alkenyl C 2-4, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyl -oxy, N - (C 1-4 alkyl }) amino, N, N - (C 1-4 alkyl) 2 amino, C 1-4 alkanoyl -amino, N- (C 1-4 alkyl) carbamoyl, N, N - (C 1-2 alkyl) 2 carbamoyl, C 1-4 alkyl -S (O) a in which a is 0 to 2, C 1-4 alkoxycarbonyl, N - (C 1-4 alkyl) sulfamoyl and N, N - (C 1-4 alkyl) 2 sulfamoyl; wherein R 12, R 13 and R 14 may be optionally independently substituted on the carbon with one or more R 17;

quad

R 15 and R 16 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, C 2-4 alkenyl , C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyl -oxy, N - (C 1-4 alkyl) amino, N, N - (C 1-4 alkyl) 2 amino, C 1-4 alkanoyl -amino, N - (C 1-4 alkyl) carbamoyl, N, N - (C 1- alkyl) 4) 2 -carbamoyl, C 1-4 alkyl -S (O) a in which a is 0 to 2, C 1-4 alkoxycarbonyl, N - (C_ alkyl {1-4) sulfamoyl and N, N - (C 1-4 alkyl) 2 sulfamoyl, sulfo, sulfino, amidino, phosphono, -P (O) (OR a) (OR ^ {b}, -P (O) (OH) (OR a), -P (O) (OH) (R a) or -P (O) (OR a) ( R b), in which R a and R b are independently selected from C 1-6 alkyl; wherein R 15 and R 16 may be optionally independently substituted on the carbon with one or more R 18;

quad

R 17 and R 18 are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy , vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N- methylcarbamoyl, N, N- dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N- methyl sulfamoyl and N, N- dimethyl ;

or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug of the same.

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According to an additional aspect of the present Invention, a compound of formula (I '') is provided:

8

in the that:

R 1 and R 2 are selected, independently, from C 1-6 alkyl;

one of R 4 and R 5 is a group of formula (IA ''):

9

quad

R 3 and R 6 and the other of R 4 and R 5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyl - oxy, N - (C 1-4 alkyl) amino, N, N - (C 1-4 alkyl) 2 amino, C 1-4 alkanoyl -amino, N - (C_ alkyl 1-4) carbamoyl, N, N - (C 1-4 alkyl) 2 carbamoyl, C 1-4 alkyl -S (O) a in which a is 0 to 2 , C 1-4 alkoxycarbonyl, N - (C 1-4 alkyl) sulfamoyl and N, N - (C 1-4 alkyl) 2 sulfamoyl; wherein R 3 and R 6 and the other of R 4 and R 5 may be optionally substituted on the carbon with one or more R 16;

quad

ring A is aryl or heteroaryl; in which the ring A is optionally substituted with one or more substituents selected from R17;

quad

R 7 is hydrogen, alkyl C 1-4, carbocyclyl or heterocyclyl; in which R 7 is optionally substituted with one or more substituents selected from R18;

R 8 is hydrogen or alkyl C 1-4;

R 9 is hydrogen or alkyl C 1-4;

quad

R 10 is hydrogen, alkyl C 1-4, carbocyclyl or heterocyclyl; in which R 10 is optionally substituted with one or more substituents selected from R19;

quad

R 11 is carboxy, sulfo, sulfino, phosphono, -P (O) (OR c) (OR d), -P (O) (OH) (OR c), -P (O) (OH) (R d) or -P (O) (OR c) (R d), in the that R c and R d are independently selected from alkyl C 1-6; or R 11 is a group of formula (IB ''):

10

in the that:

X is -N (R q) -, -N (R q) C (O) -, -O-, and -S (O) a -; where a is 0-2, and R q is hydrogen or C 1-4 alkyl;

R 12 is hydrogen or alkyl C 1-4;

quad

R 13 and R 14 are selected, independently, of hydrogen, C 1-4 alkyl, carbocyclyl or heterocyclyl; in which R 13 and R 14 can be optionally substituted, independently, with one or more substituents selected from R20;

quad

R 15 is carboxy, sulfo, sulfino, phosphono, -P (O) (OR e) (OR f), -P (O) (OH) (OR e), -P (O) (OH) (R e) or -P (O) (OR e) (R f), in the that R e and R f are independently selected from alkyl C 1-6;

p is 1-3; in which the values of R 13 may be the same or different;

q is 0-1;

r is 0-3; in which the values of R 14 may be the same or different;

m is 0-2; in which the values of R 10 may be the same or different;

n is 1-3; in which the values of R 7 may be the same or different;

quad

R 16, R 17 and R 18 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, alkenyl C 2-4, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyl -oxy, N - (C 1-4 alkyl }) amino, N, N - (C 1-4 alkyl) 2 amino, C 1-4 alkanoyl -amino, N- (C 1-4 alkyl) carbamoyl, N, N - (C 1-4 alkyl) 2 carbamoyl, C 1-4 alkyl -S (O) a in which a is 0 to 2, C 1-4 alkoxycarbonyl, N - (C 1-4 alkyl) sulfamoyl and N, N - (C 1-4 alkyl) 2 sulfamoyl; wherein R 16, R 17 and R 18 may be optionally independently substituted on the carbon with one or more R 21;

quad

R 19 and R 20 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, C 2-4 alkenyl , C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyl -oxy, N - (C 1-4 alkyl) amino, N, N - (C 1-4 alkyl) 2 amino, C 1-4 alkanoyl -amino, N - (C 1-4 alkyl) carbamoyl, N, N - (C 1- alkyl) 4) 2 -carbamoyl, C 1-4 alkyl -S (O) a in which a is 0 to 2, C 1-4 alkoxycarbonyl, N - (C_ alkyl {1-4) sulfamoyl, N, N - (C 1-4 alkyl) 2 sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P (O) (OR a) ) (OR b), -P (O) (OH) (OR a), -P (O) (OH) (R a) or -P (O) (OR < a) (R b), in which R a and R b are independently selected from C 1-6 alkyl; wherein R 19 and R 20 may be optionally independently substituted on the carbon with one or more R 22;

quad

R21 and R22 are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy , vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N- methylcarbamoyl, N, N- dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N- methyl sulfamoyl and N, N- dimethyl ;

or a pharmaceutically salt acceptable, solvate, solvate of such salt or prodrug of same.

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In the following paragraphs of the description, and in the claims, when a compound of formula is cited (I), it will be understood that this aspect also refers to compounds of formula (I ') and to compounds of formula (I' ').

In addition, the skilled person will appreciate that the numbering system differs between the compounds of formula (I) and the compounds of formula (I '). The numbering system used here hereafter refers to compounds of formula (I), but it understand that these considerations also apply to values corresponding in the formula (I ').

In this specification, the term "alkyl" includes both straight and branched chain alkyl groups, but references to individual alkyl groups, such as "propyl," are specific to the linear chain version only. For example, "C 1-6 alkyl" includes C 1-4 alkyl, C 1-3 alkyl, propyl, isopropyl and t -butyl. However, references to individual alkyl groups, such as "propyl," are specific to the linear chain version only, and references to individual branched chain alkyl groups, such as "isopropyl," are specific to the chain version. branched only. A similar convention is applied to other radicals, for example "C 1-6 phenylalkyl" would include C 1-4 phenylalkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term "halo" refers to fluoro, chloro, bromo and iodo.

When optional substituents are chosen between "one or more" groups, it is understood that this definition includes all substituents that are chosen from one of the groups specified, or substituents that are chosen from two or more of The specified groups.

"Heteroaryl" is a mono- or ring bicyclic, totally unsaturated, containing 3-12 atoms, of which at least one atom is chosen from nitrogen, sulfur or oxygen, which may, unless otherwise specified mode, be linked by carbon or nitrogen. Preferably, "heteroaryl" refers to a fully monocyclic ring unsaturated, which contains 5 or 6 atoms, or a bicyclic ring that it contains 9 or 10 atoms, of which at least one atom is chosen of nitrogen, sulfur or oxygen, which can, except that specify otherwise, be bonded by carbon or nitrogen. In another aspect of the invention, "heteroaryl" is refers to a fully unsaturated monocyclic ring, which contains 5 or 6 atoms, or a bicyclic ring containing 8, 9 or 10 atoms, of which at least one atom is chosen from nitrogen, sulfur or oxygen, which may, unless otherwise specified, be bonded by carbon or nitrogen. The examples and values suitable for the term "heteroaryl" are thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyl and quinolyl Preferably, the term "heteroaryl" refers to to thienyl or indolyl.

"Aryl" is a mono- or carbon ring bicyclic, totally unsaturated, containing 3-12 atoms Preferably, "aryl" is a monocyclic ring that it contains 5 or 6 atoms, or a bicyclic ring containing 9 or 10 atoms Suitable values for "aryl" include phenyl or Naphthyl Particularly, "aryl" is phenyl.

A "heterocyclyl" is a mono- or ring bicyclic, saturated, partially saturated or unsaturated, which it contains 3-12 atoms, of which at least one atom is chosen from nitrogen, sulfur or oxygen, which can, except otherwise specified, be linked by carbon or by nitrogen, in which a group -CH2 - can be optionally replace with a -C (O) -, or a sulfur atom annular may be optionally oxidized to form the S-oxides. Preferably, a "heterocyclyl" is a mono- or ring bicyclic, saturated, partially saturated or unsaturated, which it contains 5 or 6 atoms, of which at least one atom is chosen from nitrogen, sulfur or oxygen, which can, unless specified otherwise, be linked by carbon or nitrogen, in which a group -CH_ {2} - can be optionally substituted by a -C (O) -, or an annular sulfur atom can be optionally oxidized to form the S-oxides. The examples and Suitable values of the term "heterocyclyl" are thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl, 1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl, 2-oxo-1,3,4- (4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo [2.2.1] heptyl, 4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino, 1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, 4-pyridonyl, quinolyl and 1-isoquinolonyl.

A "carbocyclyl" is a carbon ring mono- or bicyclic, saturated, partially saturated or unsaturated, which contains 3-12 atoms, in which a group -CH_ {2} - can optionally be replaced by a -C (O) -. Preferably, "carbocyclyl" is a monocyclic ring that it contains 5 or 6 atoms, or a bicyclic ring containing 9 or 10 atoms Suitable values for "carbocyclyl" include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. Particularly, "carbocyclyl" is cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or 1-oxoindanyl.

An example of "C 1-6 alkanoyl-oxy" and "C 1-4 alkanoyl-oxy" is acetoxy. Examples of "C 1-6 alkoxycarbonyl" and "C 1-4 alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and t -butoxycarbonyl. Examples of "C 1-6 alkoxy" and "C 1-4 alkoxy" include methoxy, ethoxy and propoxy. Examples of "C 1-6 alkanoyl-amino" and "C 1-4-alkanoyl" include formamide, acetamido and propionylamino. Examples of "C 1-6 alkyl-S (O) a in which a is 0 to 2" and "C 1-4 alkyl -S (O) a in which a is 0 to 2 "include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl and ethylsulfonyl. Examples of "C 1-6 alkanoyl" and "C 1-4 alkanoyl" include C 1-3 alkanoyl, propionyl and acetyl. Examples of " N - (C 1-6 alkyl) amino" and " N - (C 1-4 alkyl) amino" include methylamino and ethylamino. Examples of " N, N - (C 1-6 alkyl) 2 amino" and " N, N - (C 1-4 alkyl) 2 amino" include di- N -methylamino, di- ( N -ethyl) amino and N -ethyl- N -methylamino. Examples of "C 2-6 alkenyl" and "C 2-4 alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C 2-6 alkynyl" and "C 2-4 alkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of " N - (C 1-6 alkyl) sulfamoyl" and " N - (C 1-4 alkyl) sulfamoyl" are N - (C 1-3 alkyl) sulfamoyl, N - (methyl) sulfamoyl and N - (ethyl) sulfamoyl. Examples of " N - (C 1-6 alkyl) 2 sulfamoyl"" N - (C 1-4 alkyl) 2 sulfamoyl" are N, N - (dimethyl) sulfamoyl and N - (methyl) - N - (ethyl) sulfamoyl. Examples of " N - (C 1-6 alkyl) carbamoyl" and " N - (C 1-4 alkyl) -carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl. Examples of " N, N - (C 1-6 alkyl) 2 -carbamoyl" and " N, N - (C 1-4 alkyl) 2 carbamoyl" are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of "C 1-6 alkoxycarbonylamino" are ethoxycarbonylamino and t -butoxycarbonylamino. Examples of " N '- (C 1-6 alkyl) ureido" are N'- methylureido and N'- ethylureido. Examples of " N - (C 1-6 alkyl) ureido" are N- methylureido and N- ethylureido. Examples of " N ', N' - (C 1-6 alkyl) 2 ureido" are N ', N ' -dimethylureido and N '-methyl- N ' -ethylureido. Examples of "N '- (alkyl C 1-6 {}) - N - (C 1-6 {}) ureido" are N' - methylureido and N -methyl- N' -propyl- N - methylureido. Examples of " N ', N' - (C 1-6 alkyl) 2 - N - (C 1-6 alkyl) ureido" are N ', N' -dimethyl- N- methylureido and N '-methyl- N ' -ethyl- N -propylureido.

A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an addition salt of acids of a compound of the invention that is sufficiently basic, for example, an acid addition salt with, for example, an inorganic or organic acid, for example hydrochloric acid, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric, or Maleic In addition, a suitable pharmaceutically acceptable salt of a compound of the invention that is sufficiently acidic is a salt of alkali metal, for example a sodium or potassium salt, a salt of alkaline earth metal, for example a calcium salt or magnesium, an ammonium salt or a salt with an organic base which gives a physiologically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

The compounds of the formula (I) can be administered in the form of a prodrug that breaks in the human or animal body to give a compound of the formula (I). Prodrugs are in vivo hydrolysable esters and in vivo hydrolysable amides of a compound of formula (I).

An in vivo hydrolysable ester of a compound of the formula (I) containing a carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester that is hydrolyzed in the body of the human or animal to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include C 1-6 alkoxy methyl esters, for example methoxymethyl, C 1-6 alkanoyl esters, for example pivaloyloxymethyl, phthalicyl esters, C 3-8 cycloalkoxy esters C 1-6 alkyl, for example 1-cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl esters, for example 5-methyl-1,3-dioxolen-2-onylmethyl, and C 1-6 alkoxy esters } -carbonyloxyethyl, for example 1-methoxycarbonyloxyethyl, and can be formed in any carboxy group in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which, as a result of in vivo hydrolysis of the ester, are broken to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolyzable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N - (dialkylaminoethyl) -N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxiacetyl. Examples of substituents in benzoyl include morpholino and piperazino linked from an annular nitrogen atom via a methylene group to position 3 or 4 of the benzoyl ring.

A suitable value for an in vivo hydrolysable amide of a compound of the formula (I) containing a carboxy group is, for example, an N- (C 1-6) alkyl - or N, N- di-alkyl ( C {6/1}) amide such as N -methyl, N -ethyl, N -propyl, N, N - dimethyl, N - ethyl-N-methyl- or N, N - diethyl amide.

Some compounds of the formula (I) may have chiral centers and / or geometric isomeric centers (E isomers and Z), and it will be understood that the invention encompasses all of those cited optical isomers, diastereoisomers and geometric isomers that possess IBAT inhibitory activity.

The invention relates to any and all the tautomeric forms of the compounds of the formula (I) that they possess IBAT inhibitory activity.

It will also be understood that certain compounds of formula (I) may exist in solvated forms as well as not solvatates, such as, for example, hydrated forms. It will be understood that the invention encompasses all said solvated forms that possess IBAT inhibitory activity.

Preferred values of R1, R2, R 3, R 4, R 5 and R 6 are as follows. Such values can be used, when appropriate, with any of the definitions, claims or embodiments defined in previous or in the future.

Preferably, R v and R w are both hydrogen.

Preferably, R 1 and R 2 are independently select from alkyl C_ {1-4}.

More preferably, R1 and R2 are independently select from ethyl or butyl.

More preferably, R1 and R2 are independently select from ethyl, propyl or butyl.

In one aspect of the invention, particularly, R 1 and R 2 are both butyl.

In a further aspect of the invention, particularly, R1 and R2 are both propyl.

In another aspect of the invention, particularly, one of R1 and R2 is ethyl and the other is butyl.

Preferably, R X and R y are independently select hydrogen or alkyl C_ {1-6}.

More preferably, R X and R y are both hydrogen.

Preferably, R z is selected from halo, amino, C 1-6 alkyl, C 1-6 alkoxycarbonylamino or N '- (C 1-6 alkyl) -ureido.

More preferably, R z is selected from chlorine, amino, t -butyl, t -butoxycarbonylamino or N '- ( t -butyl) ureido.

Preferably, v is 0 or 1.

In one aspect of the invention, more preferably, v is 0.

In one aspect of the invention, more preferably, v is 1.

In one aspect of the invention, preferably, R 4 is a group of formula (IA) (as represented previously).

In another aspect of the invention, preferably, R 5 is a group of formula (IA) (as represents above).

Preferably, R 3 and R 6 are hydrogen.

Preferably, the other of R 4 and R 5 which is not the group of formula (IA) is selected from halo, C 1-4 alkoxy or C 1-4 alkyl -S (O ) a, wherein a is 0 to 2; wherein R 4 or R 5 may be optionally substituted on the carbon with one or more R 16; wherein R 16 is independently selected from hydroxy and N, N - (C 1-4 alkyl) 2 amino.

More preferably, the other of R 4 and R 5 which is not the group of formula (IA) is selected from bromine, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesyl; wherein R 4 or R 5 may be optionally substituted on the carbon with one or more R 16; wherein R 16 is independently selected from hydroxy and N, N- dimethylamino.

Particularly, the other of R 4 and R 5 which is not the group of formula (IA) is selected from bromine, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2- ( N, N- dimethylamino) ethylthio or mesyl.

More particularly, the other of R 4 and R 5 which is not the group of formula (IA) is methylthio.

Preferably, the other of R 4 and R 5 which is not the group of formula (IA) is selected from hydrogen, halo, C 1-4 alkoxy or C 1-4 alkyl-S (O) a in which a is 0 to 2; wherein R 4 or R 5 may be optionally substituted on the carbon with one or more R 16; wherein R 16 is independently selected from hydroxy, carboxy and N, N - (C 1-4 alkyl) 2 amino.

More preferably, the other of R 4 and R 5 which is not the group of formula (IA) is selected from hydrogen, bromine, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesyl; wherein R 4 or R 5 may be optionally substituted on the carbon with one or more R 16; wherein R 16 is independently selected from hydroxy, carboxy and N, N- dimethylamino.

Particularly, the other of R 4 and R 5 which is not the group of formula (IA) is selected from hydrogen, bromine, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2 - ( N, N- dimethylamino) ethylthio or mesyl.

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In another aspect of the invention, more preferably, the other of R 4 and R 5 which is not the group of formula (IA) is selected from hydrogen, chlorine, bromine, methoxy, isopropoxy, methylthio, ethylthio or isopropylthio; wherein R 4 or R 5 may be optionally substituted on the carbon with one or more R 16; wherein R 16 is independently selected from hydroxy, carboxy and N, N- dimethylamino.

In another aspect of the invention, particularly, the other of R 4 and R 5 which is not the group of formula (IA) is selected from hydrogen, chlorine, bromine, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio or 2- ( N, N- dimethylamino) ethylthio.

In another aspect of the invention, more particularly, the other of R 4 and R 5 which is not the group of Formula (IA) is bromine or chlorine.

In another aspect of the invention, more particularly, the other of R 4 and R 5 which is not the group of Formula (IA) is methoxy.

In one aspect of the invention, preferably, Ring A is aryl.

In another aspect of the invention, preferably, ring A is heteroaryl.

When ring A is aryl, preferably, the Ring A is phenyl.

When ring A is heteroaryl, preferably, ring A is thienyl or indolyl.

Preferably, ring A is aryl or heteroaryl; wherein ring A is optionally substituted with one or more substituents selected from R17; in which

quad

R 17 is selected from halo, hydroxy or alkyl C 1-4; in which R 17 may be optionally substituted on carbon with one or more R 21; in the one who

R 21 is selected from halo.

Preferably, D is -O- or -S-.

In one aspect of the invention, more preferably, D is -O-.

In one aspect of the invention, more preferably, D is -S-.

More preferably, ring A is phenyl, thienyl or indolyl; in which ring A is optionally substituted with one or more substituents selected from halo, hydroxy or trifluoromethyl.

Particularly, ring A is selected from phenyl, 4-hydroxyphenyl, tien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 2,3-dihydroxyphenyl or indole-3-yl.

More particularly, ring A is phenyl.

In another aspect of the invention, preferably, ring A is aryl or heteroaryl; in which the ring A is optionally substituted with one or more substituents selected from R17; in which

quad

R 17 is selected from halo, hydroxy, alkyl C 1-4 or C 1-4 alkoxy; at that R 17 may be optionally substituted on carbon with one or more R 21; in which

R 21 is selected from halo.

In another aspect of the invention, more preferably, ring A is phenyl, thienyl or indolyl; at that ring A is optionally substituted with one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl.

In another aspect of the invention, particularly, ring A is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, tien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 2,3-dihydroxyphenyl or indole-3-yl.

In a further aspect of the invention, particularly, ring A is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, tien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 2,3-dihydroxyphenyl or indole-3-yl.

Preferably, R 7 is hydrogen, alkyl C 1-4 or carbocyclyl.

More preferably, R 7 is hydrogen, methyl or phenyl.

Particularly, R 7 is hydrogen.

In one aspect of the invention, preferably, R 8 is hydrogen.

In another aspect of the invention, preferably, R 8 is C 1-4 alkyl.

In another aspect of the invention, more preferably, R 8 is hydrogen or methyl.

In one aspect of the invention, preferably, R 9 is hydrogen.

In another aspect of the invention, preferably, R 9 is C 1-4 alkyl.

In another aspect of the invention, more preferably, R 9 is hydrogen or methyl.

Preferably, R 10 is hydrogen.

In one aspect of the invention, preferably, R 11 is carboxy, sulfo, sulfino, phosphono, -P (O) (OR c) (OR d), -P (O) (OH) (OR c), -P (O) (OH) (R d) or -P (O) (OR c) (R d), in the that R c and R d are independently selected from alkyl C_ {1-6}.

In another aspect of the invention, preferably, R 11 is a group of formula (IB) (as per represents above).

Preferably, R 11 is carboxy, -P (O) (OH) (OR c), or a group of formula (IB) (as per represents above).

More preferably, R 11 is carboxy, -P (O) (OH) (OEt), or a group of formula (IB) (as per represents above).

In another aspect of the invention, preferably, R 11 is carboxy, sulfo, -P (O) (OH) (OR c) in which R c is selected from C 1-4 alkyl, or a group of formula (IB) (according to is represented above).

Preferably, X is -NH- or -NHC (O) -.

More preferably, X is -NHC (O) -.

In one aspect of the invention, preferably, R 12 is hydrogen.

In another aspect of the invention, preferably, R 12 is C 1-4 alkyl.

In another aspect of the invention, more preferably, R 12 is hydrogen or methyl.

Preferably, R 13 is hydrogen, alkyl C 1-4 or carbocyclyl; in which R 13 is optionally substituted with one or more selected substituents of R 20; in which

R 20 is hydroxy.

More preferably, R 13 is hydrogen, methyl or phenyl; wherein R 13 is optionally substituted with one or more substituents selected from R20; in which

R 20 is hydroxy.

Particularly, R 13 is hydrogen, hydroxymethyl or phenyl.

More particularly, R 13 is hydrogen or hydroxymethyl.

In another aspect of the invention, preferably, R 13 is hydrogen, alkyl C 1-4 or carbocyclyl; in which R 13 is optionally substituted with one or more selected substituents of R 20; in which

quad

R 20 is hydroxy, carboxy, carbocyclyl or amino; wherein R 20 may be optionally substituted on the carbon with one or more R22;

R 22 is hydroxy.

In another aspect of the invention, more preferably, R 13 is hydrogen, methyl, ethyl, butyl or phenyl; wherein R 13 is optionally substituted with one or more substituents selected from R20; in which

quad

R 20 is hydroxy, carboxy, phenyl or amino; at that R 20 may be optionally substituted on carbon with one or more R22; R 22 is hydroxy.

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In another aspect of the invention, particularly, R 13 is hydrogen, hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl or phenyl.

In a further aspect of the invention, preferably, R 13 is hydrogen, alkyl C 1-4 or carbocyclyl; in which R 13 is optionally substituted with one or more selected substituents of R 20; in which

quad

R 20 is hydroxy, carboxy, carbocyclyl, heterocyclyl or amino; wherein R 20 may optionally be substituted on carbon with one or more R22;

R 22 is hydroxy.

In a further aspect of the invention, more preferably, R 13 is hydrogen, methyl, ethyl, butyl or phenyl; wherein R 13 is optionally substituted with one or more substituents selected from R20; in which

quad

R 20 is hydroxy, carboxy, phenyl, imidazolyl or Not me; wherein R 20 may be optionally substituted on carbon with one or more R22;

R 22 is hydroxy.

In a further aspect of the invention, particularly, R 13 is hydrogen, hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl, imidazol-5-ylmethyl or phenyl.

In a further aspect of the invention, preferably, R 13 is hydrogen, alkyl C 1-4, carbocyclyl or R 23; in which R 13 is optionally substituted with one or more substituents selected from R20; in which

quad

R 20 is hydroxy, alkyl C 1-4 -S (O) a where a is 0, C 1-4 alkoxy, amino, carbocyclyl, heterocyclyl or mercapto; in which R 20 can be optionally independently substituted on carbon with one or more R22;

R22 is selected from hydroxy; Y

R 23 is carboxy.

In a further aspect of the invention, more preferably, R 13 is hydrogen, methyl, ethyl, butyl or phenyl or R 23; wherein R 13 is optionally substituted with one or more substituents selected from R20; in which

quad

R 20 is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto; wherein R 20 may optionally be independently substituted on carbon with one or more R22;

R22 is selected from hydroxy; Y

R 23 is carboxy.

In a further aspect of the invention, particularly, R 13 is hydrogen, carboxy, hydroxymethyl, mercaptomethyl, methoxymethyl, methylthiomethyl, 2-methylthioethyl, 4-aminobutyl, 4-hydroxybenzyl, imidazol-5-ylmethyl or phenyl.

In another aspect, more particularly, R13 it is methylthiomethyl, methylsulfinylmethyl or methylsulfonylmethyl.

Preferably, R 14 is hydrogen.

In another aspect of the invention, preferably, R 14 is selected from hydrogen, alkyl C 1-4 or carbocyclyl; in which said alkyl C_ {1-4} or carbocyclyl may optionally be substituted with one or more substituents selected from R20; Y

R 20 is hydroxy.

In another aspect of the invention, more preferably, R 14 is selected from hydrogen, methyl or phenyl; wherein said methyl or phenyl may optionally be substituted with one or more substituents selected from R20; Y

R 20 is hydroxy.

In another aspect of the invention, particularly, R 14 is hydrogen, phenyl or hydroxymethyl.

Particularly, R 15 is carboxy or sulfo

In one aspect of the invention, more particularly, R 15 is carboxy.

In another aspect of the invention, more particularly, R 15 is sulfo.

Preferably, R 15 is carboxy, sulfo, -P (O) (OR e) (OR f), -P (O) (OH) (OR e), -P (O) (OH) (R e) or -P (O) (OR e)
(R f), in which R e and R f are independently selected from C 1-4 alkyl.

More preferably, R 15 is carboxy, sulfo, -P (O) (OR e) (OR f), -P (O) (OH) (OR e), -P (O) (OH) (R e) or -P (O) (OR e) (R f), in the that R e and R f are independently selected from methyl or ethyl.

Preferably, R 15 is carboxy, sulfo, -P (O) (OEt) (OEt), -P (O) (OH) (OEt), -P (O) (OH) (Me) or -P (O) (OEt) (Me).

Preferably, R 15 is carboxy, sulfo, phosphono, -P (O) (OR e) (OR f), -P (O) (OH) (OR e), -P (O) (OH) (R e) or -P (O) (OR e)
(R f), in which R e and R f are independently selected from C 1-4 alkyl, or R 15 is a group of formula (IC) (as depicted above).

More preferably, R 15 is carboxy, sulfo, phosphono, -P (O) (OR e) (OR f), -P (O) (OH) (OR e), -P (O) (OH) (R e) or -P (O) (OR e) (R f), in which R e and R f are independently selected from methyl or ethyl, or R 15 is a group of formula (IC) (as depicted above).

Preferably, R 15 is carboxy, sulfo, phosphono, -P (O) (OE t) (OE t), -P (O) (O t -Bu) (O t -Bu ), -P (O) (OH) (OEt), -P (O)
(OH) (Me) or -P (O) (OEt) (Me), or R 15 is a group of formula (IC) (as depicted above).

In one aspect of the invention, preferably, R 15 is a group of formula (IC) (as represented previously).

In another aspect of the invention, preferably, R 15 is not a group of formula (IC) (as represents above).

In one aspect of the invention, preferably, R 15 is carboxy.

In another aspect of the invention, preferably, R 15 is sulfo.

In another aspect of the invention, preferably, R 15 is -P (O) (OH) (OEt).

In another aspect of the invention, preferably, R 15 is -P (O) (OH) (Me).

In another aspect of the invention, preferably, R 15 is -P (O) (OEt) (Me).

In one aspect of the invention, preferably, R 24 is hydrogen.

In another aspect of the invention, preferably, R 24 is C 1-4 alkyl.

Preferably, R 25 is hydrogen.

Preferably, R 26 is carboxy.

Preferably, p is 1 or 2; in which the R13 values may be the same or different.

In one aspect of the invention, more preferably, p is 1.

In another aspect of the invention, more preferably, p is 2; in which the values of R 13 can Be the same or different.

In a further aspect of the invention, more preferably, p is 3; in which the values of R 13 can Be the same or different.

In one aspect of the invention, preferably, q is 0.

In a further aspect of the invention, preferably, q is 1.

In one aspect of the invention, preferably, r is 0.

In one aspect of the invention, more preferably, r is 1.

In another aspect of the invention, more preferably, r is 2; in which the values of R 14 can Be the same or different.

In a further aspect of the invention, more preferably, r is 3; in which the values of R 14 can Be the same or different.

Preferably, m is 0.

In another aspect of the invention, preferably, m is 0 or 1.

Preferably, n is 1.

In another aspect of the invention, preferably, n is 1 or 2.

Preferably, z is 1.

The group of formula (IA ') in which R 7 is hydrogen, methyl or phenyl, n is 1, ring A is phenyl, thienyl or indolyl; wherein ring A is optionally substituted with one or more substituents selected from halo, hydroxy or trifluoromethyl, m is 0, and R 9 is carboxy, -P (O) (OH) (OR c) or a group of formula (IB).

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The group of formula (IA) in which:

D is -O- or -S-;

quad

Ring A is phenyl, thienyl or indolyl; in which ring A is optionally substituted with one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl;

R 7 is hydrogen, methyl or phenyl;

R 8 is hydrogen or methyl;

R 9 is hydrogen or methyl;

R 10 is hydrogen;

m is 0-2, in which the values of R 10 may be the same or different; Y

quad

R 11 is carboxy, -P (O) (OH) (OEt), or a group of formula (IB) (as depicted in claim one);

quad

The group of formula (IB '), in which R 10 is hydrogen, hydroxymethyl or phenyl, p is 1 or 2; in which the values of R 10 may be the same or different, and R 11 is carboxy or sulfo

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The formula group (IB) in which:

R 12 is hydrogen or methyl;

quad

R 13 is hydrogen, methyl, ethyl, butyl or phenyl or R 23; wherein R 13 is optionally substituted with one or more substituents selected from R20; R 20 is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto; in which R 20 may be optionally substituted on carbon with one or more hydroxy; R 23 is carboxy;

X is -NH- or -NHC (O) -;

quad

R 14 is selected from hydrogen, methyl or phenyl; wherein said methyl or phenyl may optionally be substituted with one or more substituents selected from hydroxy;

quad

R 15 is carboxy, sulfo, phosphono, -P (O) (OR e) (OR f), -P (O) (OH) (OR e), -P (O) (OH) (R e) or -P (O) (OR e) (R f), in the that R e and R f are independently selected from methyl or ethyl, or R 15 is a group of formula (IC) (as represents in claim 1);

p is 1-3, in which the values of R 13 may be the same or different;

q is 0-1; Y

r is 0-3, in which the values of R 14 may be the same or different;

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The formula group (IC) in which

R 24 is hydrogen;

R 25 is hydrogen;

R 26 is carboxy; Y

z is 1;

or a pharmaceutically salt acceptable, solvate, solvate of such salt or prodrug of same.

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Therefore, in an additional aspect of the invention, a compound of formula (I ') is provided as represents above, in which:

R 1 and R 2 are selected, independently, from ethyl or butyl;

R 3 and R 6 are hydrogen;

quad

R 4 is selected from halo, C 1-4 alkoxy or C 1-4 alkyl -S (O) a in which a is 0 to 2; wherein R 4 may be optionally substituted on the carbon with one or more R 16; wherein R 16 is independently selected from hydroxy and N, N - (C 1-4 alkyl) 2 amino;

R 5 is a group of formula (IA ');

quad

ring A is aryl or heteroaryl; in which the ring A is optionally substituted with one or more substituents selected from R17; in which

quad

R 17 is selected from halo, hydroxy or alkyl C 1-4; in which R 17 may be optionally substituted on carbon with one or more R 21; in the one who

R 21 is selected from halo;

R 7 is hydrogen, alkyl C 1-4 or carbocyclyl;

R 11 is carboxy, -P (O) (OH) (OR c), or a group of formula (IB ') (as depicted above);

quad

R 13 is hydrogen, alkyl C 1-4 or carbocyclyl; in which R 13 is optionally substituted with one or more selected substituents of R 20; in which

R 20 is hydroxy;

R 15 is carboxy or sulfo;

p is 1 or 2; in which the values of R 13 They can be the same or different;

m is 0; Y

n is 1;

or a pharmaceutically salt acceptable, solvate, solvate of such salt or prodrug of same.

       \ vskip1.000000 \ baselineskip
    

Therefore, in an additional aspect of the invention, a compound of formula (I ') is provided as represents above, in which:

R 1 and R 2 are both butyl, or one of R 1 and R 2 is ethyl and the other is butyl;

R 4 is methylthio;

R 5 is a group of formula (IA ') (as per represents above);

R 3 and R 6 are hydrogen;

ring A is phenyl;

R 7 is hydrogen;

R 11 is a group of formula (IB ') (as represents above);

R 13 is hydrogen or hydroxymethyl;

R 15 is carboxy or sulfo;

p is 1 or 2; in which the values of R 13 They can be the same or different;

m is 0;

n is 1;

or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug far del same.

       \ vskip1.000000 \ baselineskip
    

Therefore, in another additional aspect of the invention, a compound of formula (I '') is provided, as represents above, in which:

R 1 and R 2 are selected, independently, from ethyl or butyl;

R 3 and R 6 are hydrogen;

quad

R 4 is selected from halo, C 1-4 alkoxy or C 1-4 alkyl -S (O) a in which a is 0 to 2; wherein R 4 may be optionally substituted on the carbon with one or more R 16; wherein R 16 is independently selected from hydroxy and N, N - (C 1-4 alkyl) 2 amino;

R 5 is a group of formula (IA '');

quad

Ring A is aryl or heteroaryl; in which the ring A is optionally substituted with one or more substituents selected from R17;

R 7 is hydrogen, alkyl C 1-4 or carbocyclyl;

R 8 is hydrogen or methyl;

R 9 is hydrogen or methyl;

R 11 is carboxy, -P (O) (OH) (OR c), or a group of formula (IB '') (as represented previously);

X is -NH- or NHC (O) -;

R 12 is hydrogen or methyl;

quad

R 13 is hydrogen, alkyl C 1-4 or carbocyclyl; in which R 13 is optionally substituted with one or more selected substituents of R 20;

R 14 is hydrogen;

R 15 is carboxy or sulfo;

quad

R 17 is selected from halo, hydroxy, alkyl C 1-4 or C 1-4 alkoxy; at that R 17 may be optionally substituted on carbon with one or more R 21;

quad

R 20 is hydroxy, carboxy, carbocyclyl or amino; wherein R 20 may be optionally substituted on the carbon with one or more R22;

R 21 is selected from halo;

R 22 is hydroxy;

p is 1-3; in which the values of R 13 may be the same or different.

q is 0-1;

r is 0-3; in which the values of R 14 may be the same or different; and in which if q is 1, r is not 0;

m is 0-2; Y

n is 1-3;

or a pharmaceutically salt acceptable, solvate, solvate of such salt or prodrug of same.

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Therefore, in another additional aspect of the invention, a compound of formula (I) is provided, as represents above, in which:

R v and R w are both hydrogen;

R 1 and R 2 are selected, independently, from C 1-4 alkyl;

R X and R Y are both hydrogen;

R z is selected from halo, amino, C 1-6 alkyl, C 1-6 alkoxycarbonylamino or N '- (C 1-6 alkyl) ureido;

v is 0 or 1;

R 3 and R 6 are hydrogen;

quad

one of R 4 and R 5 is a group of formula (IA) (as depicted above) and the other is selected from hydrogen, halo, C 1-4 alkoxy or C 1- alkyl 4 -S (O) a in which a is 0 to 2; wherein R 4 or R 5 may be optionally substituted on the carbon with one or more R 16; wherein R 16 is independently selected from hydroxy, carboxy and N, N - (C 1-4 alkyl) 2 amino;

D is -O- or -S-;

R 7 is hydrogen, methyl or phenyl;

R 8 is hydrogen or methyl;

quad

ring A is aryl or heteroaryl; in which the ring A is optionally substituted with one or more substituents selected from R17; wherein R 17 is selected from halo, hydroxy, C 1-4 alkyl or alkoxy C 1-4; in which R 17 may be optionally substituted on carbon with one or more R 21; in which R 21 is selected from halo;

R 9 is hydrogen or methyl;

R 10 is hydrogen;

quad

R 11 is carboxy, -P (O) (OH) (OR c) in which R c is selected from C 1-4 alkyl, or a group of formula (IB) (as represented previously);

R 12 is hydrogen or methyl;

X is NH- or -NHC (O) -;

quad

R 13 is hydrogen, alkyl C 1-4, carbocyclyl or R 23; in which R 13 is optionally substituted with one or more substituents selected from R20; wherein R 20 is hydroxy, alkyl C 1-4 -S (O) a where a is 0, C 1-4 alkoxy, amino, carbocyclyl, heterocyclyl or mercapto; in which R 20 can be optionally independently substituted on carbon with one or more R22; R22 is selected from hydroxy; Y R 23 is carboxy;

quad

R 14 is selected from hydrogen, alkyl C 1-4 or carbocyclyl; in which said alkyl C_ {1-4} or carbocyclyl may optionally be substituted with one or more substituents selected from R20; Y R 20 is hydroxy;

quad

R 15 is carboxy, sulfo, phosphono, -P (O) (OR e) (OR f), -P (O) (OH) (OR e), -P (O) (OH) (R e) or -P (O) (OR e) (R f), in the that R e and R f are independently selected from alkyl C 1-4, or R 15 is a group of formula (IC) (as depicted above);

R 24 is hydrogen;

R 25 is hydrogen;

R 26 is carboxy;

p is 1-3; in which the values of R 13 may be the same or different;

q is 0-1;

r is 0-3; in which the values of R 14 may be the same or different;

m is 0-2; in which the values of R 10 may be the same or different;

n is 1-2; in which the values of R 7 may be the same or different;

z is 0-1; in which the values of R 25 may be the same or different;

or a pharmaceutically salt acceptable, solvate, solvate of such salt or prodrug of same.

       \ vskip1.000000 \ baselineskip
    

In another aspect of the invention, compounds Preferred of the invention are any one of the Examples or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug of them.

In one aspect of the invention, a compound of formula (I) selected from Examples 8, 9, 46, 56, 59, 60, 61, 62, 66 and 69, or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug thereof.

In another aspect of the invention, it is provided a compound of formula (I), which is Example 73, 74, 95, 96, 97, 98, 99 and 100, or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug thereof.

In another aspect of the invention, compounds Preferred of the invention are any one of Examples 43, 50, 51 and 52, or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug thereof.

In a further aspect of the invention, Preferred compounds of the invention are any one of the Examples 43, 46, 50, 51, 56, 58, 59, 61, 62, 63, 69, 81, 83, 85, 94, 97, 98, 108, 109, 110, 111 or 117.

Preferred aspects of the invention are those related to the compound of formula (I) or a salt pharmaceutically acceptable thereof.

Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug thereof, method which comprises (in the that the variable groups are, unless otherwise specified mode, as defined in formula (I)):

Procedure 1): oxidize a Benzothiazepine of formula (II):

eleven

Procedure 2): for compounds of formula (I) wherein D is -O-, -NRa or -S-, react a compound of formula (IIIa) or (IIIb):

12

with a compound of formula (IV):

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13

       \ vskip1.000000 \ baselineskip
    

in which L is a group scrollable;

Procedure 3): react an acid of formula (Va) or (Vb):

       \ vskip1.000000 \ baselineskip
    

14

       \ vskip1.000000 \ baselineskip
    

or an activated derivative thereof, with an amine of formula (SAW):

       \ vskip1.000000 \ baselineskip
    

fifteen

       \ vskip1.000000 \ baselineskip
    

Procedure 4): for compounds of formula (I) in which R 11 is a group of formula (IB), to react a compound of formula (I), wherein R 11 is carboxy, with a amine of formula (VII):

       \ vskip1.000000 \ baselineskip
    

16

       \ newpage
    

Procedure 5): for compounds of formula (I) wherein R 11 is carboxy, deprotect a compound of formula (VIIIa):

17

or (VIIIb):

18

in which R P is alkyl C 1-4;

Procedure 6): for compounds of formula (I) wherein R 11 is a group of formula (IB), and R 15 is carboxy, deprotect a compound of formula (IXa):

       \ vskip1.000000 \ baselineskip
    

19

       \ newpage
    

or (IXb):

       \ vskip1.000000 \ baselineskip
    

twenty

       \ vskip1.000000 \ baselineskip
    

in which R P is alkyl C 1-4;

Procedure 7) for compounds of formula (I) in which one of R 4 and R 5 is selected, independently of alkyl C_ {1-4} -thio optionally substituted on carbon with one or more R 16, react a compound of formula (Xa) or (Xb):

       \ vskip1.000000 \ baselineskip
    

twenty-one

       \ vskip1.000000 \ baselineskip
    

in which L is a group movable, with a thiol of formula (XI):

(XI) R y -H

wherein R y is alkyl C_ {1-4} -thio optionally substituted on carbon with one or more R 16;

Procedure 8) for compounds of formula (I) in which R 15 is a group of formula (IC), to react a compound of formula (IXa) or (IXb), wherein R P is hydrogen, with a compound of formula (XII):

       \ vskip1.000000 \ baselineskip
    

22

       \ newpage
    

Procedure 9): for compounds of formula (I) wherein R 11 is a group of formula (IB), and R 15 is a group of formula (IC) and R 26 is carboxy, deprotect a compound of formula (XIIIa):

       \ vskip1.000000 \ baselineskip
    

2. 3

       \ vskip1.000000 \ baselineskip
    

or (XIIIb):

       \ vskip1.000000 \ baselineskip
    

24

       \ vskip1.000000 \ baselineskip
    

and R P is alkyl C 1-4;

Procedure 10): for compounds of formula (I) in which X is -N (R q) C (O) -, do reacting a compound of formula (XIVa):

       \ vskip1.000000 \ baselineskip
    

25

       \ newpage
    

or (XIVb):

26

with a compound of formula (XV):

27

and then, if necessary or desirable:

i)

convert a compound of the formula (I) in another compound of the formula (I);

ii)

delete any of the groups protectors;

iii)

form a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug.

The skilled person will also appreciate that they can also use similar procedures corresponding to the above procedures for preparing compounds of formula (I ') and compounds of formula (I' '), in which the definitions of Variable groups may differ.

L is a scrollable group; adequate values for L they are, for example, a halogen or sulfonyloxy group, for example a chlorine, bromine, methanesulfonyloxy or toluene-4-sulfonyloxy.

R p is C 1-4 alkyl. Preferably, R p is methyl or ethyl. More preferably, R p is methyl.

The specific reaction conditions for Previous reactions are as follows.

Procedure 1): the benzotiepines of the formula (II) can be oxidized under standard oxidation conditions of the sulfur; for example, using hydrogen peroxide and acid trifluoroacetic acid at a temperature in the range of 0 ° C until reflux temperature, preferably at or near the temperature ambient.

The compounds of formula (II) can be prepare according to Scheme I for compounds of formula (I) in the that R x and R y are hydrogen. The skilled person will appreciate that when R x and R y are not both hydrogen, it is necessary manipulate the following synthetic route using procedures known by the skilled person.

       \ newpage
    

Scheme one

28

in which L is a scrollable group as defined above, and Y is a scrollable group, by example halo.

The compounds of formulas (IIa) and (IIc) are commercially available compounds, or are known in the bibliography, or are prepared by standard procedures known in the art.

Procedure 2): the formula alcohols (IIIa) or (IIIb) can be reacted with compounds of formula (IV) in the presence of a base, for example a base inorganic such as sodium carbonate, or an organic base, such as Hunig's base, in the presence of a suitable solvent such as acetonitrile, dichloromethane or tetrahydrofuran, at a temperature in the range of 0 ° C to reflux temperature, preferably at or near the reflux temperature.

The compounds of formulas (IIIa) or (IIIb) are they can prepare similarly to the compounds of formula (II) (but in which R 4 or R 5 is hydroxy), followed by the step of oxidation of Procedure 1).

The compounds of formula (IV) are compounds commercially available, or are known in the literature, or are prepare by standard procedures known in the technique.

Procedure 3), Procedure 4), Procedure 8) and Procedure 10): acids and amines are can be coupled together in the presence of a coupling reagent suitable. They can be used as suitable reagents of coupling, standard peptide coupling reagents known in the art, or, for example, carbonyldiimidazole and dicyclohexylcarbodiimide, optionally in the presence of a catalyst, such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base, for example triethylamine, pyridine, or 2,6-di-alkyl pyridines, such as 2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The reaction of coupling can be conveniently performed at a temperature in the range from -40 to 40 ° C.

Derivatives of suitable activated acids they include acid halides, for example acid chlorides, and esters active, for example pentafluorophenyl esters. The reaction of these types of compounds with amines is well known in the technique, for example they can be reacted in the presence of a base, as described above, and in a solvent suitable, as described above. The reaction can be done. conveniently perform at a temperature in the range of -40 up to 40 ° C.

The compounds of formulas (Va) or (Vb), in the that D is -O-, -NR a, -S-, can be prepared according to the Scheme 2:

       \ vskip1.000000 \ baselineskip
    

Scheme 2

29

       \ vskip1.000000 \ baselineskip
    

in which L is a group scrollable as defined previously.

The compounds of formulas (Va) and (Vb), in the that D is -SO- or -SO2 -, can be prepared by oxidizing the compounds resulting from formulas (Va) and (Vb) from the Scheme 2, in which D is -S-.

The compounds of formulas (Va) or (Vb), in the that D is -CH2 -, can be prepared according to Scheme 3.

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

(Scheme turns to page next)

       \ newpage
    

Scheme 3

30

Compounds of formulas (XIVa) or (XIVb) are they can prepare by any of the procedures described here in which R 11 is a group of formula (IB), but in those that (IB) is a group of formula (XVI):

31

The compounds of formulas (Vc), (VI), (VII), (XII), (XV) and (XVI) are commercially available compounds, or are known in the literature, or are prepared by standard procedures known in the art.

Procedure 5), Procedure 6) and Procedure 9): esters of formulas (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb) can be checked out using conditions standards such as those described below, for example they can deprotect with sodium hydroxide in methanol, at temperature ambient.

The esters of formulas (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb) can be prepared by any of the above procedures for the preparation of compounds of formula (I), but in which R 11, R 15 or R 26 is alkoxy C 1-4 -carbonyl.

Procedure 7): the compounds of formulas (Xa) and (Xb) can be reacted with thiols of formula (XI) in the presence of a base, for example an inorganic base such as sodium carbonate, or an organic base such as Hunig's base, in the presence of a suitable solvent such as DMF or THF, at a temperature in the range of 0 ° C to the temperature of Reflux.

The compounds of formulas (Xa) and (Xb) can be prepare by any of the above procedures to the preparation of the compounds of formula (I), but in which one of R 4 and R 5 is L.

The compounds of formula (XI) are compounds commercially available, or are known in the literature, or are prepare by standard procedures known in the technique.

It will be appreciated that some of the various ring substituents, in the compounds herein invention, can be introduced by substitution reactions aromatic standards, or can be generated by modifications conventional functional groups, either before or immediately after the procedures mentioned above, and as such are included in the aspect of the process of the invention. Such modifications and reactions include, for example, the introduction of a substituent by means of a reaction of aromatic substitution, substituent reduction, alkylation of substituents and oxidation of substituents. Reagents and the reaction conditions for such procedures are fine known in the chemical art. The particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of a acyl group using, for example, an acyl halide and an acid of Lewis (such as aluminum trichloride), under Friedel conditions Crafts; the introduction of an alkyl group using a halide of alkyl and a Lewis acid (such as aluminum trichloride) in Friedel Crafts conditions; and the introduction of a group halogen Particular examples of modifications include the reduction of a nitro group to an amino group, for example by catalytic hydrogenation with a nickel catalyst, or by treatment with iron in the presence of hydrochloric acid, heated; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl.

It will also be appreciated that in some of the reactions mentioned here may be necessary / desirable to protect any of the sensitive groups in the compounds. The cases in those that are necessary protection, or desirable, and methods suitable for protection are known to experts in the technique. Conventional protecting groups can be used according to the standard practice (for an illustration see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Of this mode, if the reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in Some of the reactions mentioned here.

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t- butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protective groups will necessarily vary with the choice of the protective group. Thus, for example, an acyl group, such as an alkanoyl or alkoxycarbonyl group, or an aroyl group, can be removed, for example, by hydrolysis with a suitable base, such as an alkali metal hydroxide, for example hydroxide of lithium or sodium hydroxide. Alternatively, an acyl group, such as a t -butoxycarbonyl group, can be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric acid, or trifluoroacetic acid, and an arylmethoxycarbonyl group, such as a group benzyloxycarbonyl can be removed, for example, by hydrogenation on a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example boron tris (trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which can be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

A protective group suitable for a group hydroxy is, for example, an acyl group, for example a group alkanoyl such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The conditions of deprotection for the previous protecting groups necessarily They will vary with the choice of the protective group. In this way, by example, an acyl group, such as an alkanoyl group or a group aroyl, can be removed, for example, by hydrolysis with a suitable base, such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide. As an alternative, a group arylmethyl, such as a benzyl group, can be removed, by example, by hydrogenation on a catalyst such as palladium on coal.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl group or an ethyl group, which can be removed, for example, by hydrolysis with a base, such as sodium hydroxide, or for example a t -butyl group, which can be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group, which can be removed, for example, by hydrogenation on a catalyst such as palladium on coal.

Protective groups can be removed in any convenient stage in the synthesis, using techniques Conventionals well known in the chemical art.

As stated hereinbefore, the compounds defined in the present invention possess IBAT inhibitory activity. These properties can be evaluated, for example, using an in vitro assay to study the effect on bile acid uptake in cells transfected with IBAT (Smith L., Price-Jones MJ, Hugnes KT and Jones NRA; J Biomolecular Screening, 3 , 227-230), or in vivo studying the effect of radioactively labeled bile acid absorption in mice / rats (Lewis MC, Brieaddy LE and Root C., J., J Lip Res 1995, 36, 1098-1105).

According to a further aspect of the invention, provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, as defined herein previously, in association with a diluent or vehicle pharmaceutically acceptable.

The composition may be in a suitable form. for oral administration, for example as a tablet or capsule, for parenteral injection (which includes intravenous, subcutaneous, intramuscular, intravascular or infusion) as a solution sterile, suspension or emulsion, for topical administration as a ointment or cream, or for rectal administration as a suppository.

In general, the above compositions are can be prepared conventionally using excipients conventional.

The compound of formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, will normally be administered to an animal of warm blood at a unit dose within the range 5-5000 mg per square meter of body area of the animal, that is, approximately 0.1-100 mg / kg, or 0.01-50 mg / kg, and this usually provides a Therapeutically effective dose. A unit dosage form, such as a tablet or a capsule, it will usually contain, by example, 1-250 mg of active ingredient. Preferably, a daily dose is used in the range of 1-50 mg / kg In another aspect, a dose is used daily in the range of 0.02-20 mg / kg. Without However, the daily dose will necessarily vary depending on the treated host, of the particular route of administration, and of the severity of the disease being treated. Consequently, the Optimal dose can be determined by the doctor who is treating Any particular patient.

According to an additional aspect of the present invention, a compound of formula (I), or a salt is provided pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, as defined hereinbefore, for use in a method of prophylactic or therapeutic treatment of an animal of hot blood, just like man.

It has been found that the compounds defined in the present invention, or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, are effective IBAT inhibitors, and consequently are valuable in the treatment of diseases associated with states hyperlipidemic

Thus, according to this aspect of the invention, a compound of the formula (I), or a salt is provided pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, as defined hereinbefore, for use as a medicine

According to another characteristic of the invention, provides the use of a compound of the formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, as defined hereinbefore, in the manufacture of a medicament for use in the production of an effect IBAT inhibitor in a warm-blooded animal, such as the man.

According to another characteristic of the invention, provides the use of a compound of the formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, as defined hereinbefore, in the manufacture of a drug for use in the treatment of conditions hyperlipidemic in a warm-blooded animal, such as the man.

According to another characteristic of the invention, provides the use of a compound of the formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, as defined hereinbefore, in the manufacture of a drug for use in the treatment of conditions dyslipidemic and disorders such as hyperlipidemia, hypertriglyceridemia, hyperbetalipoproteinemia (elevated LDL), hyperprebetalipoproteinemia (elevated VLDL), hyperkylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia e hypoalphalipoproteinemia (low HDL), in a blood animal Hot, just like man.

According to another characteristic of the invention, provides the use of a compound of the formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, as defined hereinbefore, in the manufacture of a medicament for use in the treatment of different pathological states such as atherosclerosis, arteriosclerosis, arrhythmia, hypertrombotic states, dysfunction vascular, endothelial dysfunction, heart failure, coronary heart disease, cardiovascular disease, heart attack myocardium, angina pectoris, peripheral venous insufficiencies, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurysms, stenosis, restenosis, vascular plaques, vascular fat stretch marks, leukocyte, monocyte and / or macrophage infiltration, thickening of intimacy, thinning of the stocking, infectious trauma and Surgical and vascular thrombosis, stroke and ischemic attacks transient, in a warm-blooded animal, such as the man.

According to another characteristic of the invention, provides the use of a compound of the formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, as defined hereinbefore, in the manufacture of a medicament for use in the treatment of atherosclerosis, coronary heart disease, myocardial infarction, angina pectoris, peripheral venous insufficiencies, stroke and transient ischemic attacks, in a warm-blooded animal, just like man

According to an additional feature of this aspect of the invention, a method for producing a IBAT inhibitory effect on a warm-blooded animal, such as the man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof.

According to an additional feature of this aspect of the invention, a method of treating is provided hyperlipidemic states in a warm-blooded animal, such as the man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof.

According to an additional feature of this aspect of the invention, a method of treating is provided dyslipidemic states and disorders such as hyperlipidemia, hypertriglyceridemia, hyperbetalipoproteinemia (elevated LDL), hyperprebetalipoproteinemia (elevated VLDL), hyperkylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia e hypoalphalipoproteinemia (low HDL), in a warm-blooded animal, such as man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof.

According to an additional feature of this aspect of the invention, a method of treating is provided different pathological states such as atherosclerosis, arteriosclerosis, arrhythmia, hypertrombotic states, dysfunction vascular, endothelial dysfunction, heart failure, coronary heart disease, cardiovascular disease, heart attack myocardium, angina pectoris, peripheral venous insufficiencies, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurysms, stenosis, restenosis, vascular plaques, vascular fat stretch marks, leukocyte, monocyte and / or macrophage infiltration, thickening of intimacy, thinning of the stocking, infectious trauma and Surgical and vascular thrombosis, stroke and ischemic attacks transients, which need such treatment, which includes administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof.

According to an additional feature of this aspect of the invention, a method of treating is provided atherosclerosis, coronary heart disease, myocardial infarction, angina pectoris, peripheral venous insufficiencies, stroke and transient ischemic attacks in a warm-blooded animal, such as man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof.

There are signs that an IBAT inhibitor can be potentially useful in the treatment and / or prevention of gallstones According to an additional feature of this aspect of the invention, a method for treating and / or providing prevent gallstones in a warm-blooded animal, such as the man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof.

The dose size required for the therapeutic or prophylactic treatment will necessarily vary depending on the host treated, the route of administration and of the severity of the disease to be treated. For example, a unit dose in the range of 1-100 mg / kg, preferably 1-50 mg / kg.

IBAT inhibitory activity defined here previously it can be applied as a single therapy, or it can involve, in addition to a compound of the invention, one or more different substances and / or treatments. Such joint treatment is can achieve by simultaneous, sequential or separate from the individual components of the treatment. According this aspect of the invention, a product is provided Pharmaceutical comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, as defined hereinbefore, and a additional IBAT inhibitor substance, as defined here above, and an additional hypolipidemic agent, for the joint treatment of hyperlipidemia.

In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, can be administered in association with an HMG CoA reductase inhibitor,  or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable HMG inhibitors CoA reductase, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, are Statins well known in the art. The particular statins they are fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin, mevastatin and acid (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methyl-sulfonyl) amino] pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxyhept-6 -enoic  (rosuvastatin), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof. A statin particular is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof. A More particular statin is the calcium salt of atorvastatin. A even more particular statin is acid (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3,5-dihydroxyhept-6-enoic  (rosuvastatin), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof. One more statin Particular is the calcium salt of rosuvastatin.

In a further aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, can be administered in association with an HMG CoA reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, and / or with a bile acid binder, thereby avoiding a possible risk of excess bile acids in the colon caused by inhibition of the transport system of bile acids present in the ileum. An excess of bile acids in the visceral contents can cause diarrhea. Thus, the present invention also provides a treatment of a possible side effect, such as diarrhea, in patients during therapy comprising the compound of
formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof.

An HMG inhibitor CoA reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, will reduce, through this action, the available endogenous cholesterol for the synthesis of bile acids, and will have an additive effect on combination with the compound of formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, in the reduction of lipids.

The appropriate bile acid binders, for such combination therapy, they are resins, such as cholestyramine and colestipol. An advantage is that the dose of bile acid binder can be kept lower than the therapeutic dose for the treatment of cholesterolemia in a individual treatment comprising only one binder of bile acids. It could also be avoided, by a low dose of bile acid binder, any of the possible side effects caused by poor patient tolerance at the therapeutic dose.

Therefore, in an additional feature of the invention, a method for producing an effect is provided IBAT inhibitor in a warm-blooded animal, such as the man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in simultaneous, sequential or separated with an effective amount of an HMG inhibitor Co-A reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug of the same.

Therefore, in an additional feature of the invention, a method for producing an effect is provided IBAT inhibitor in a warm-blooded animal, such as the man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in simultaneous, sequential or separated with a bile acid binder.

Therefore, in an additional feature of the invention, a method for producing an effect is provided IBAT inhibitor in a warm-blooded animal, such as the man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in simultaneous, sequential or separated with an effective amount of an HMG inhibitor Co-A reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, in simultaneous, sequential or separate administration with a bile acid binder.

Therefore, in an additional feature of the invention, a method for treating states is provided hyperlipidemic in a warm-blooded animal, such as the man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in simultaneous, sequential or separated with an effective amount of an HMG inhibitor Co-A reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug of the same.

Therefore, in an additional feature of the invention, a method for treating states is provided hyperlipidemic in a warm-blooded animal, such as the man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in simultaneous, sequential or separated with an effective amount of an acid binder biliary

Therefore, in an additional feature of the invention, a method for treating states is provided hyperlipidemic in a warm-blooded animal, such as the man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in simultaneous, sequential or separated with an effective amount of an HMG inhibitor Co-A reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, in simultaneous, sequential or separate administration with a bile acid binder.

According to a further aspect of the invention, provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, and an HMG inhibitor CoA reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, in association with a pharmaceutically diluent or carrier acceptable.

According to a further aspect of the invention, provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, and a binder of bile acids, in association with a diluent or carrier pharmaceutically acceptable.

According to a further aspect of the invention, provides a pharmaceutical composition comprising compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, and an HMG inhibitor CoA reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, and a bile acid binder, in association with a vehicle or pharmaceutically acceptable diluent.

According to an additional aspect of the present invention, a kit is provided comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, and an HMG inhibitor CoA reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug of the same.

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According to an additional aspect of the present invention, a kit is provided comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, and a binder of bile acids.

According to an additional aspect of the present invention, a kit is provided comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, and an HMG inhibitor CoA reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, and a bile acid binder.

According to an additional aspect of the present Invention, a kit is provided comprising:

to)

a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in a first unit dosage form;

b)

a HMG CoA-reductase inhibitor, or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, in a second unit dosage form; Y

C)

a container means for containing said first and second forms of dosage.

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According to an additional aspect of the present Invention, a kit is provided comprising:

to)

a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in a first unit dosage form;

b)

a bile acid binder, in a second dosage form unitary; Y

C)

a container means for containing said first and second forms of dosage.

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According to an additional aspect of the present Invention, a kit is provided comprising:

to)

a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in a first unit dosage form;

b)

a HMG CoA-reductase inhibitor, or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, in a second dosage form unitary;

C)

a bile acid binder, in a third dosage form unitary; Y

d)

a container means for containing said first, second and third dosage forms.

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According to an additional aspect of the present Invention, a kit is provided comprising:

to)

a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, together with a diluent or pharmaceutically acceptable carrier, in a first unit dosage form;

b)

a HMG CoA-reductase inhibitor, or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, in a second dosage form unitary;

C)

a container means for containing said first and second forms of dosage.

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According to an additional aspect of the present Invention, a kit is provided comprising:

to)

a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, together with a diluent or pharmaceutically acceptable carrier, in a first unit dosage form;

b)

a bile acid binder, in a second dosage form unitary; Y

C)

a container means for containing said first and second forms of dosage.

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According to an additional aspect of the present Invention, a kit is provided comprising:

to)

a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, together with a diluent or pharmaceutically acceptable carrier, in a first unit dosage form;

b)

a HMG CoA-reductase inhibitor, or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, in a second dosage form unitary;

C)

a bile acid binder, in a third dosage form unitary; Y

d)

a container means for containing said first, second and third dosage forms.

According to another characteristic of the invention, provides the use of a compound of formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, and an HMG inhibitor CoA reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, in the manufacture of a medicament for use in the production of a IBAT inhibitory effect on a warm-blooded animal, such as the man.

According to another characteristic of the invention, provides the use of a compound of formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, and a bile acid binder, in the manufacture of a medicament for use in the production of an effect IBAT inhibitor in a warm-blooded animal, such as the man.

According to another characteristic of the invention, provides the use of a compound of formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, and an HMG inhibitor CoA reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, and a bile acid binder, in the manufacture of a medication for use in the production of an IBAT inhibitory effect in a warm-blooded animal, just like man.

According to another characteristic of the invention, provides the use of a compound of formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, and an HMG inhibitor CoA reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidemic states in a warm-blooded animal, such as the man.

According to another characteristic of the invention, provides the use of a compound of formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, and a bile acid binder, in the manufacture of a drug for use in the treatment of conditions hyperlipidemic in a warm-blooded animal, such as the man.

According to another characteristic of the invention, provides the use of a compound of formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, an HMG inhibitor CoA reductase, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, and a bile acid binder, in the manufacture of a medication for use in the treatment of hyperlipidemic states in a warm-blooded animal, just like man.

The treatment methods of the human body or of the animal body through therapy are not included within the Scope of the present invention.

According to an additional aspect of the present invention, a combination treatment is provided that comprises administering an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, optionally together with a pharmaceutically acceptable carrier or diluent, with the simultaneous, sequential or separate administration of an amount effective of an HMG CoA reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, optionally together with a vehicle or pharmaceutically acceptable diluent, to a blood animal hot, like man, who needs such treatment therapeutic.

According to an additional aspect of the present invention, a combination treatment is provided that comprises administering an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, optionally together with a pharmaceutically acceptable carrier or diluent, with the simultaneous, sequential or separate administration of an amount Effective of a bile acid binder, optionally together with a pharmaceutically acceptable carrier or diluent, to an animal warm-blooded, just like man, who needs such therapeutic treatment

According to an additional aspect of the present invention, a combination treatment is provided that comprises administering an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, optionally together with a pharmaceutically acceptable carrier or diluent, with the simultaneous, sequential or separate administration of an amount effective of an HMG CoA reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, optionally together with an excipient pharmaceutically acceptable, with simultaneous administration, sequential or separated from an effective amount of a binder of bile acids, optionally together with a vehicle or diluent pharmaceutically acceptable, to a warm-blooded animal, such Like man, who needs such therapeutic treatment.

According to another additional aspect of the present invention, a combination treatment is provided that comprises administering an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, optionally together with a pharmaceutically acceptable carrier or diluent, with the simultaneous, sequential or separate administration of one or more of the following agents selected from:

->

a CETP inhibitor (ester transfer protein from cholesteryl), for example those cited and described in the document WO 00/38725, page 7, line 22, to page 10, line 17;

->

a cholesterol absorption antagonist, for example azetidinones such as SCH 58235 and those described in US document 5,767,115;

->

a MTP inhibitor (microsomial transfer protein), by example those described in Science, 282, 751-54, 1998;

->

a derivative of fibric acid, for example clofibrate, gemfibrozil, fenofibrate, ciprofibrate and bezafibrate;

->

a Nicotinic acid derivative, for example nicotinic acid (niacin), acipimox and niceritrol;

->

a phytosterolic compound, for example stanols;

->

probucol;

->

a compound against obesity, for example orlistat (EP document 129,748) and sibutramine (documents GB 2,184,122 and US 4,929,629);

->

a antihypertensive compound, for example an enzyme inhibitor angiotensin converter (ACE), a receptor antagonist angiotensin II, an andrenergic blocker, a blocker alpha-andrenergic, a blocker beta-andrenergic, a blocker mixed alpha / beta-andrenergic, a stimulant andrenergic, a calcium channel blocker, a diuretic or a vasodilator;

->

insulin;

->

sulfonylureas, including glibenclamide, tolbutamide;

->

metformin; I

->

acarbose;

or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, optionally together with a pharmaceutical carrier or diluent acceptable, to a warm-blooded animal, such as man, that need such treatment therapeutic.

Particular ACE inhibitors, or salts pharmaceutically acceptable, solvates, solvates of such salts or prodrugs thereof, including active metabolites, which can be use in combination with a compound of formula (I), include but They are not limited to the following compounds: alaceprile, alatriopril, calcium altiopril, ancovenin, benazepril, hydrochloride benazepril, benazeprilat, benzoylcaptopril, captopril, captopril-cysteine, Captopril-glutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril, enalaprilat, Enapril, Epicaptopril, Foroximitin, Phosphenoprile, Fosenopril, Sodium Fosenoprile, Fosinopril, Sodium Fossinoprile, Fossinoprilat, fosinoprilic acid, glycopyrile, hemorrhoid-4, idrapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril, liciumina A, liciumina B, mixanprilo, moexiprile, moexiprilat, moveltiprile, muracein A, muracein B, muracein C, pentopril, perindopril, perindoprilat, pivalopril, pivoprile, quinapril, quinapril hydrochloride, quinaprilat, ramiprile, ramiprilat, spirapril, spirapril hydrochloride, spiraprilat, spiroprile, spiroprile hydrochloride, temocapril, hydrochloride of temocapril, teprotide, trandolapril, trandolaprilat, utibaprilo, zabiciprilo, zabiciprilat, zofenoprilo and zofenoprilat. Preferred ACE inhibitors for use in the present invention they are ramiprile, ramiprilat, lisinopril, enalapril and enalaprilat. The most preferred ACE inhibitors for use herein invention are ramiprile and ramiprilat.

Preferred angiotensin II antagonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for use in combination with a compound of formula (I), include, but are not limited to, the Compounds: Candesartan, Candesartan Cilexetil, Losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan. Particularly preferred angiotensin II antagonists, or pharmaceutically acceptable derivatives thereof, for use in The present invention are candesartan and candesartan cilexetil.

In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, can be administered in association with an agonist of PPAR alpha and / or gamma, or salts pharmaceutically acceptable, solvates, solvates of such salts or prodrugs thereof. PPAR alpha and / or gamma agonists suitable, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, are well known in the art. These include the compounds described in WO 01/12187, WO 01/12612, WO 99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med Chem, 1996, 39, 665, Expert Opinion on Therapeutic Patents, 10 (5), 623-634 (in particular the compounds described in Patent Applications listed on page 634), and J Med Chem, 2000, 43, 527. Particularly, an agonist of PPAR alpha and / or gamma refers to WY-14643, clofibrate, fenofibrate, bezafibrate, GW 9578, troglitazone, pioglitazone, rosiglitazone, eglitazone, proglitazone, BRL-49634, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433. Particularly, an agonist of PPAR alpha and / or gamma refers to acid (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} -ethoxy) phenyl] propanoic acid, and pharmaceutically acceptable salts thereof.

Therefore, in an additional feature of the invention, a method for producing an effect is provided IBAT inhibitor in a warm-blooded animal, such as the man, who needs such treatment, which includes administering, to said animal, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in simultaneous, sequential administration or separated with an effective amount of a PPAR alpha agonist and / or gamma, or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof.

Therefore, in an additional feature of the invention, a method for treating states is provided hyperlipidemic in a warm-blooded animal, such as the man, who needs such treatment, which includes administering, to said animal, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in simultaneous, sequential administration or separated with an effective amount of a PPAR alpha agonist and / or gamma, or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof.

According to another aspect of the invention, provides a pharmaceutical composition, which comprises a compound  of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, and a PPAR agonist alpha and / or gamma, or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in association with a Diluent or pharmaceutically acceptable carrier.

According to another aspect of the invention, provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, and an agonist of PPAR alpha and / or gamma, or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug of it.

According to another aspect of the invention, provides a kit that includes:

to)

a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in a first unit dosage form;

b)

a PPAR alpha and / or gamma agonist, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, in a second unit dosage form; Y

C)

a container means for containing said first and second forms of dosage.

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According to another aspect of the invention, provides a kit that includes:

to)

a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, together with a diluent or pharmaceutically acceptable carrier, in a first unit dosage form;

b)

a PPAR alpha and / or gamma agonist, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, in a second unit dosage form; Y

C)

a container means for containing said first and second forms of dosage.

According to another characteristic of the invention, provides the use of a compound of formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, and an agonist of PPAR alpha and / or gamma, or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, in the manufacture of a medicament for use in the production of an inhibitory effect of IBAT in an animal of Hot blood, just like man.

According to another characteristic of the invention, provides the use of a compound of the formula (I), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, an agonist of PPAR alpha and / or gamma, or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidemic states in a blood animal Hot, just like man.

According to another aspect of the invention, provides a combination treatment comprising the administration of an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, optionally together with a vehicle or pharmaceutically acceptable diluent, with administration simultaneous, sequential or separate from an effective amount of a PPAR alpha and / or gamma agonist, or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, optionally together with a pharmaceutical carrier or diluent acceptable, to a warm-blooded animal, such as man, that need such therapeutic treatment.

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In addition to their use in therapeutic medicine, the compounds of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, are also useful as pharmacological tools in the development and standardization of test systems. in vitro and in vivo for the evaluation of the effects of IBAT inhibitors in laboratory animals, such as cats, dogs, rabbits, monkeys, rats and mice, as part of the investigation of new therapeutic agents.

Many of the intermediates described herein are new, and are thus provided as an additional feature of the invention. For example, the compounds of formulas (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb) show IBAT inhibitory activity when tested in the in vitro assays cited above, and thus They are claimed as a feature of the invention.

Thus, in an additional feature of the invention, a compound of formula (VIIIa) is provided, (VIIIb), (IXa), (IXb), (XIIIa) or (XIIIb), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug of it.

Therefore, according to an additional aspect of the invention, a pharmaceutical composition is provided which comprises a compound of formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, as defined herein previously, in association with a diluent or vehicle pharmaceutically acceptable.

According to a further aspect of the invention, provides a compound of the formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof, as defined here above, for use in a treatment method prophylactic or therapeutic of a warm-blooded animal, such as the man.

Thus, according to this aspect of the invention, a compound of the formula (VIIIa) is provided, (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb), or a salt pharmaceutically acceptable, solvate, solvate of such salt or a prodrug thereof, as defined hereinbefore, for use as a medicine

According to another characteristic of the invention, provides the use of a compound of the formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb), or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, as defined here above, in the manufacture of a medication for use in the production of an IBAT inhibitory effect in a warm-blooded animal, just like man.

According to another characteristic of the invention, provides the use of a compound of the formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb), or a pharmaceutically salt acceptable, solvate, solvate of such salt or a prodrug thereof, as defined here above, in the manufacture of a medication for use in the treatment of hyperlipidemic states in a warm-blooded animal, just like man.

According to an additional feature of this aspect of the invention, a method for producing a IBAT inhibitory effect on a warm-blooded animal, such as the man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug of it.

According to an additional feature of this aspect of the invention, a method of treating is provided hyperlipidemic states in a warm-blooded animal, such as the man, who needs such treatment, which includes administering to said animal an effective amount of a compound of formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb), or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug of it.

In the other previous features of the pharmaceutical composition, procedure, method, use and of the manufacture of medicines, the alternative and preferred embodiments of the compounds of the invention described here.

Examples

The invention will now be illustrated in the Following Non-limiting Examples, in which they may be used, when  appropriate, standard techniques known to the chemist expert, and techniques analogous to those described in these Examples, and in which, unless otherwise stated:

(i) evaporations were carried out by vacuum rotary evaporation, and the procedures of treatment were carried out after solids removal residuals, such as drying agents, by filtration;

(ii) all reactions were carried out in an inert atmosphere at room temperature, typically in the 18-25 ° C range, with HPLC grade solvents under anhydrous conditions, unless otherwise stated;

(iii) column chromatography (by means of ultrafast procedure) was performed on silica gel 40-63 µm (Merck);

(iv) yields are given for illustration only, and are not necessarily the maximum obtainable;

(v) the structures of the final products of formula (I) were generally confirmed by resonance nuclear magnetic (NMR) (usually proton) and techniques mass spectral; the values of chemical shifts of the magnetic resonance were measured in deuterated CDCl3 (unless otherwise stated), on the delta scale (ppm downstream of tetramethylsilane); proton data is given, unless otherwise stated; the spectra are recorded on a Varian Mercury-300 spectrometer MHz, Varian Unity plus-400 MHz, Varian Unity plus-600 MHz or in a Varian Inova-500 MHz, unless otherwise established mode; the data was recorded at 400 MHz; and the multiplicities of the peaks are shown as follows: s, singlet; d, double up; dd, double double; t, triplet; tt, triple triplet; q, quartete; tq, triple quartet; m, multiplet; br, width; ABq, AB quartet; ABd, double of AB; ABdd, AB doublet double; dABq, double AB's quartet; the LCMS were registered in a Waters device ZMD, LC column xTerra MS C_ {8} (Waters), detection with a device equipped with a set of HP 1100 detector diodes MS; mass spectra (MS) (loop) were recorded in a VG Platform II device (Fisons Instruments), equipped with a HP-1100 MS detector diode assembly; except to be established otherwise, the given mass ion is (MH +);

(vi) unless other details are specified in the text, high-performance analytical liquid chromatography Performance (HPLC) was performed in Prep LC 2000 (Waters), Cromasil C8, 7 µm, (Akzo Nobel); MeCN and 10 mM deionized water ammonium acetate as mobile phases, with a composition adequate;

(vii) usually, intermediates do not fully characterized, and purity was assessed by thin layer chromatography (TLC), HPLC, infrared analysis (IR), MS or NMR;

(viii) when the solutions dried, the drying agent was sodium sulfate;

(ix) when an "ISOLUTE" column is cited, this means a column containing 2 g of silica, the silica contained in a 6 ml disposable syringe, and supported by a porous disk of 54 \ ring {A} pore size, obtained from International Sorbent Technology with the name "ISOLUTE"; "ISOLUTE" is a registered trademark;

(x) the following abbreviations can be used here in the above or in the following:

DCM

dichloromethane;

DMF

N, N- dimethylformamide;

TBTU

O-benzotriazol-1-yl- N, N, N ', N'- tetramethyluronium tetrafluoroborate;

EtOAc

EtOAC;

MeCN

acetonitrile

TFA

trifluoroacetic acid;

IPA

isopropanol;

DIPEA

diisopropylethylamine; Y

THF

tetrahydrofuran.

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Example 1 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxyl-2,3,4,5- tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - ((R) -1'-phenyl-1'-methoxycarbonylmethyl) carbamoylmethoxy] -2,3,4 , 5-tetrahydro-1,5-benzothiazepine (Method 29; 300 mg, 0.46 mmol) in methanol (5 ml). NaOH (100 mg in 0.2 ml of water) was added to the solution, and the mixture was stirred at room temperature for 1 hour. Acetic acid (0.3 ml) was added. The solvent was evaporated under reduced pressure, and the residue was extracted with DCM / water. The DCM layer was separated, dried and evaporated under reduced pressure to give 270 mg of the title compound (92%). NMR, (500 MHz) 0.7-0.8 (m, 6H), 1.0-1.6 (m, 12H), 2.1 (s, 3H) 3.2 (br s, 2H), 3.6-3.8 (m, 2H), 4.6 (s, 2H), 5.6 (d, 1H), 6.6 (s, 1H), 6.9-7.5 (m, 11H), 7.8 (d, 1H).

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Examples 2-9

The following compounds were synthesized by the procedure of Example 1, using the material of appropriate game

32

3. 4

Example 10 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-1- [ N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoyl] ethoxy} -2 , 3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- {1- [ N - ((R) -1'-phenyl-1'-methoxycarbonylmethyl) carbamoyl] -
ethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 33; 103 mg, 0.15 mmol) in a mixture of THF and H2O (2: 1.3 ml). LiOH (7 mg, 0.3 mmol) was added, and the mixture was stirred for 7 hours at room temperature. Most of the solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC, using MeCN and ammonium acetate buffer (45:55) as eluent, to give 97 mg (96%). NMR (DMSO-d 6) 0.60-0.80 (m, 6H), 0.90-1.60 (m, 11H), 3.15-3.45 (m, 2H), 3, 50-3.90 (m, 2H), 4.95-5.25 (m, 2H), 6.85-7.55 (m, 12H), 8.55-8.95 (m, 1H).

Examples 11-16

The following compounds were synthesized by the procedure of Example 10, using the material of appropriate game

36

37

Example 17 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [ N - ((S) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2,3,4 , 5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [ N - ((S) -1'-phenyl-1'-methoxycarbonylmethyl) carbamoylmethoxy] -2,3 , 4,5-tetrahydro-1,5-benzothiazepine (Method 46; 60 mg, 0.091 mmol) in THF (1 ml), and added to a solution of lithium hydroxide monohydrate (12.6 mg, 0.29 mmol ) in water (1 ml). The mixture was stirred occasionally for 30 minutes. A solution of 2M HCl (0.3 ml) was added, and the aqueous layer was extracted with DCM. The organic layer was washed once with brine, dried, filtered and evaporated under reduced pressure, to give 48 mg of the title compound (82%). NMR (CD 3 OD) 0.73-0.84 (m, 6H), 1.0-1.6 (m, 8H), 3.27 (br s, 2H), 3.60-3, 90 (m, 2H), 4.71 (ABq, 2H), 5.47-5.55 (m, 1H), 7.02 (br t, 1H), 7.08-7.17 (m, 3H ), 7.25-7.46 (m, 7H), 7.52 (s, 1H), 8.43 (d, NH); m / z 643.5.

Examples 18-21

The following compounds were synthesized by the procedure of Example 17, using the material of appropriate game

38

39

Example 22 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [ N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2,3,4 , 5-tetrahydro-1,5-benzothiazepine

The title compound was synthesized from 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [ N - ((R) -1'-phenyl-1'-methoxycarbonylmethyl ) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 61) by the procedure of Example 17, except that the aqueous layer was extracted with EtOAc. The product was purified by preparative HPLC, using a gradient of MeCN / ammonium acetate buffer (5/95 to 100/0) as eluent. NMR 0.75-0.83 (m, 6H), 1.0-1.25 (m, 4H), 1.32-1.52 (m, 3H), 1.55-1.70 (m, 1H), 3.20 (ABq, 2H), 3.65-3.83 (m, 2H), 4.62 (ABq, 2H), 5.68 (d, 1H), 7.04-7.15 (m, 4H), 7.3-7.5 (m, 8H), 7.87 (br d, 1H); m / z 643.1.

Example 23 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- ( N - {(S) -1'-phenyl-1 '- [ N ' - (2) ammonium salt -sulfoethyl) carbamoyl] methyl} -carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [ N - {(S) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2,3 ,
4,5-tetrahydro-1,5-benzothiazepine (Example 17; 48 mg, 0.075 mmol) and 2-aminoethanesulfonic acid (17 mg, 0.14 mmol) in DMF (2 ml) and DIPEA (0.052 ml, 0.30 mmoles). The mixture was stirred for 15 minutes at 60 ° C. TBTU (31 mg, 0.097 mmol) was added, and the mixture was stirred for 2 hours at 60 ° C. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC using a gradient of MeCN / ammonium acetate buffer (5/95 to 100/0) as eluent. Lyophilization gave 4 mg of the title compound (7%). NMR (CD 3 OD) 0.75-0.83 (m, 6H), 0.95-1.65 (m, 8H), 2.85-3.0 (m, 2H), 3.27 (br s, 2H), 3.5-3.9 (m, 4H), 4.72 (ABq, 2H), 5.48 (s, 1H), 7.02 (br t, 1H), 7, 09-7.15 (m, 3H), 7.25-7.52 (m, 8H); m / z 750.3.

Examples 24-37

The following compounds were prepared by The same procedure. The acid (1 equivalent) was dissolved in 1 ml of THF, and was added to a solution of lithium hydroxide monohydrate (12.6 mg, 2.9-6.6 equivalents) in water (1 ml). The mixture was stirred occasionally, and after 1.5-6 hours the check out was finished (from according to LC-MS). A solution of 2M HCl was added (0.3 ml).

Examples 24-33

The reaction mixture was placed on a syringe filled with Hydramatrix®. The product was eluted with DCM. The DCM was dried, filtered and evaporated under reduced pressure. He product was purified by preparative HPLC, using a MeCN / ammonium acetate buffer gradient (5/95 to 100/0) as eluent

Examples 34-37

The aqueous layer was extracted twice with DCM. The organic layer was dried, filtered and evaporated under pressure reduced

40

42

43

44

Four. Five

46

Example 38 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2,3,4 , 5-tetrahydro-1,5-benzothiazepine

The 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2,3,4 , 5-tetrahydro-l, 5-benzothiazepine  (Example 22; 50 mg, 0.078 mmol) was dissolved in DMF (1.5 ml). Be Sodium methanethiolate (20 mg, 0.29 mmol) was added, and the mixture was stirred for 1.5 hours at 50 ° C. Acetic acid (40 mg) was added, and The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC, using MeCN / acetate buffer ammonium (45:55) as eluent to give 29 mg of the title compound (61%). NMR (DMSO-d6): 0.7-0.8 (m, 6H), 0.9-1.6 (m, 8H), 2.2 (s, 3H), 3.1-3.7 (m, 4H), 4.6-4.8 (m, 3H), 6.7 (s, 1H), 6.8-7.4 (m, 11H), 8.3 (d, 1H).

Example 39 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-ethylthio-8- [ N - ((R ') - 1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2,3, 4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2,3 ,4,
5-tetrahydro-1,5-benzothiazepine (Example 22; 50 mg, 0.078 mmol), ethanothiol (99 mg, 1.59 mmol) and cesium carbonate (253 mg, 0.78 mmol) at DMF (5 m), and the mixture was stirred for 30 hours at 44 ° C. The solvent was filtered, evaporated under reduced pressure. The residue was purified by preparative HPLC, using MeCN / ammonium acetate buffer (45:55) as eluent. The residue was purified by column chromatography using DCM: methanol (100: 15) to give the title compound 15 mg (31%). NMR (300 MHz, CD 3 OD) 0.7-0.85 (m, 6H), 1.0-1.6 (m, 11H), 2.65 (q, 2H), 3.2 ( s, 2H), 3.7 (br s, 2H), 4.6 (q, 2H), 5.3 (s, 1H), 6.75 (s, 1H), 6.9-7.5 ( m, 11H).

Example 40 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7- (2-hydroxyethylthio) -8- [ N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2 , 3,4,5-te-trahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [N - ((R) -1'-phenyl-l'-carboxymethyl) carbamoylmethoxy] -2,3 ,4,
5-tetrahydro-1,5-benzothiazepine (Example 22; 50 mg, 0.078 mmol), 2-mercaptoethanol (281 mg, 3.59 mmol) and cesium carbonate (228 mg, 0.7 mmol) to DMF (5 ml ), and the mixture was stirred for 9 hours at 70 ° C. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC, using MeCN / ammonium acetate buffer (45:55) as eluent. The collected fractions were lyophilized to give 20 mg of the title compound (40%). NMR (300 MHz, CD3 OD) 0.75-0.85 (m, 6H), 1.0-1.6 (m, 8H), 2.9 (t, 2H), 3.2 ( s, 2H), 3.55 (t, 2H), 3.7 (br s, 2H), 4.65 (q, 2H), 5.3 (s, 1H), 6.9 (s, 1H) , 6.95-7.5 (m, 11H).

Example 41 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7- (2- N ', N ' -dimethylamino-ethylthio) -8- [ N - ((R) -1'-phenyl-1 '-carboxymethyl) carbamoyl-methoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2,3 ,4,
5-tetrahydro-1,5-benzothiazepine (Example 22; 50 mg, 0.078 mmol), dimethylaminoethanethiol hydrochloride (99 mg, 0.94 mmol), potassium carbonate (129 mg, 0.94 mmol), DIPEA (100 mg , 0.77 mmol) and sodium borohydride (35 mg, 0.93 mmol) at DMF (10 ml), and the mixture was stirred for 24 hours at 85 ° C. The solvent was filtered and evaporated under reduced pressure. The residue was purified twice by preparative HPLC, using MeCN / ammonium acetate buffer (40:60) as eluent. The collected fractions were lyophilized to give 15 mg of the title compound (30%). NMR (300 MHz, CD 3 OD) 0.75-0.85 (m, 6H), 1.0-1.65 (m, 8H), 2.65 (s, 6H), 3.05 ( t, 2H), 3.2 (t, 2H), 3.3 (s, 2H), 3.75 (br s, 2H), 4.75 (s, 2H), 5.2 (s, 1H) , 6.95-7.4 (m, 11), 7.5 (s, 1H).

Example 42 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-isopropylthio-8- [ N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy-2,3,4, 5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2,3 ,4,
5-tetrahydro-1,5-benzothiazepine (Example 22; 50 mg, 0.078 mmol), 2-propanothiol (126 mg, 1.65 mmol), cesium carbonate (152 mg, 0.47 mmol), sodium borohydride ( 25 mg, 0.66 mmol) to DMF (5 ml), and the mixture was stirred for 5 minutes at 100 ° C. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC, using MeCN / ammonium acetate buffer (45:55) as eluent. The collected fractions were lyophilized to give 15 mg of the title compound (30%). NMR (300 MHz, DMSO-d 6) 0.7-0.85 (m, 6H), 0.95-1.65 (m, 14H), 3.3 (s, 2H), 3.7 (br s, 2H), 4.75 (dd, 2H), 5.05 (br s, 1H), 6.75-7.4 (m, 12H), 8.5 (br s, 1H).

Example 43 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [ N ' - (carboxymethyl) carbamoyl] methyl} carbamoyl -methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

It dissolved 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -1'-phenyl-1 '- [N' - (t-butoxycarbonylmethyl) -carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 63; 120 mg, 0.17 mmol) in DCM (2 ml). TFA (0.7 ml), and the mixture was heated at room temperature for 3 hours. The reaction mixture was evaporated under reduced pressure. The residue is purified by preparative HPLC, using MeCN / buffer ammonium acetate (50:50) as eluent, to give 95 mg of title compound (85%). NMR (300 MHz, DMSO-d 6) 0.7-0.8 (m, 6H), 0.9-1.6 (m, 12H), 2.2 (s, 3H) 3.2-3.3 (m, 2H), 3.5-3.8 (m, 4H), 4.8 (ABq, 2H), 5.6 (d; 1H), 6.7 (s, 1H), 6.8-7.5 (m, 11H), 8.5-8.7 (m, 2H).

Examples 44-49

The following compounds were synthesized by the procedure of Example 43, using the material of appropriate game

47

48

49

Example 50 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [ N ' - (2-sulfoethyl) ammonium salt ) carbamoyl] methyl} -carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

It dissolved 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 22; 150 mg, 0.30 mmol) and acid 2 - ((2'R) -2'-amino-2'-phenylethanylamino) ethanesulfonic acid (Method 28; containing DIPEA hydrochloride, 150 mg, 0.36 mmol) in DMF (6 ml). DIPEA (0.2 ml, 1.15 mmol) and TBTU (114 mg, 0.36 mmol), and the mixture was stirred for 2 hours at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC, using a MeCN / ammonium acetate buffer gradient (5/95 to 100/0) as eluent, to give 73 mg of the title compound (32%). NMR (CD 3 OD) 0.75-0.85 (m, 6H), 1.0-1.3 (m, 8H), 1.3-1.6 (m, 4H), 2.16 (s, 3H), 2.85-3.0 (m, 2H), 3.24 (br s, 2H) 3.5-3.85 (m, 4H), 4.70 (ABq, 2H), 5.47 (s, 1H), 6.71 (s, 1H), 6.97 (br t, 1H), 7.11 (br d, 2H), 7.23-7.45 (m, 8H); m / z 746.2.

Example 51 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [ N ' - (2 - ammonium salt -sulfoethyl) carbamoyl] -methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine was dissolved
(Method 17; 49 mg, 0.10 mmol) and 2 - ((2'R) -2'-amino-2'-phenylethylamino) ethanesulfonic acid (Method 28; containing DIPEA hydrochloride; 52 mg, 0.12 mmol) in DMF (2 ml). DIPEA (0.071 ml, 0.41 mmol) and TBTU (39 mg, 0.12 mmol) were added, and the mixture was stirred for 2 hours at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC, using a gradient of MeCN / ammonium acetate buffer (5/95 to 100/0) as eluent, to give 59 mg of the title compound (78%). NMR (CD 3 OD) 0.74-0.90 (m, 6H), 0.98-1.3 (m, 4H), 1.35-1.67 (m, 4H), 2.16 (s, 3H), 2.85-3.02 (m, 2H), 3.23 (br s, 2H) 3.52-3.90 (m, 4H), 4.70 (ABq, 2H), 5.47 (s, 1H), 6.71 (s, 1H), 6.96 (br t, 1H), 7.09 (br d, 2H), 7.21-7.48 (m, 8H) ; m / z 718.4.

Example 52 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [ N - (carboxymethyl) carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [N- (ethoxycarbonylmethyl) -carbamoyl) was dissolved ]
methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 72; 44 mg, 0.063 mmol) in THF: H2O, 1: 1, (2 ml), and added sodium hydroxide (1 M, 0.126 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with HCl (1 M), diluted to 10 ml, and extracted with DCM (3 x 10 ml). The combined organic layers were dried over magnesium sulfate, and the solvent was evaporated to give 33 mg of the title compound (78%). NMR (300 MHz) 0.78-0.85 (m, 6H), 1.02-1.70 (m, 8H), 2.20 (s, 3H), 3.15 / 3.21 (ABq, 2H), 3.78 (m, 2H), 3.94 / 4.20 (dABq, 2H), 4.64 (q, 2H), 5.91 (d, 1H), 6.65 (s, 1H ), 6.98-7.52 (m, 11H), 8.17 (d, 1H).

Example 53 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [ N - (1''- carboxy- 1 '' - phenylmethyl) carbamoyl] methyl} -carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

The title compound was synthesized from 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N - {(R) -1'-phenyl-1'- [ N - (1 '' - methoxycarbonyl-1 '' - phenylmethyl) carbamoyl] -methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 73) by the procedure of Example 52. NMR (500 MHz) 0.76-0.84 (m, 6H), 1.05-1.73 (m, 8H), 2.14 (s, 3H), 3.16 (m, 2H), 3 , 74 (m, 2H), 4.48 (m, 2H), 5.53 (d, 2H), 5.96 (d, 2H), 6.63 (s, 1H), 6.97-7, 48 (m, 13H), 7.86 (m, 1H), 8.17 (m, 1H).

Example 54 1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8- {1- [ N - ((R) -? -Carboxybenzyl) carbamoyl] ethoxy} -2,3,4 , 5-tetrahydro-1,5-benzothiazenin

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- (1- [ N - ((R) -1'-phenyl-1'-carboxymethyl) -carbamoyl] ethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 10, 0.050 g, 7.6x10-5 mol) in DMF (4 ml) sodium thiomethylate ( 0.021 g, 3.0x10-4 moles), and the solution was stirred for 4 hours at room temperature.The mixture was concentrated, and the residue was partitioned between water and ether.The aqueous layer was extracted twice more with ether, and the combined organic extracts were dried over magnesium sulfate, concentrated and purified by HPLC.The title compound was obtained in a yield of 0.030 g (63%) as a white solid NMR (CD 3 OD) ) 0.75-0.90 (m, 6H), 1.00-1.30 (m, 4H), 1.40-1.70 (m, 7H), 2.15 (d, 3H), 3 , 10-3.30 (m, 2H), 3.55-3.95 (m, 2H), 4.80-4.95 (m, 2H), 5.30 (d, 1H), 6.70 -7.50 (m, 12H); m / z 625.3.

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Example 55 1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8 - {α- [ N - ((R) - α-carboxybenzyl) carbamoyl] benzyloxy} -2,3, 4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8 - {α- [ N - ((R) -? -Carboxybenzyl) carbamoyl] -benzyl-
xi} -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 11; 0.018 g, 2.5x10-5 mol) in DMF (3 ml) sodium thiomethylate (0.007 g, 1.0x10 -4 moles), and the solution was stirred for 4 hours at room temperature. The mixture was concentrated, and the residue was partitioned between water and ether. The aqueous layer was extracted twice more with ether, and the combined organic extracts were dried over magnesium sulfate, concentrated and purified by HPLC. The title compound was obtained in a yield of 0.015 g (89%) as a white solid. NMR (CD 3 OD) 0.70-0.85 (m, 6H), 1.00-1.25 (m, 4H), 1.35-1.65 (m, 4H), 2.20 (d, 3H), 3.10-3.20 (m, 2H), 3.50-3.85 (m, 2H), 5.30 (d, 1H), 5.80 (d, 1H), 6.70 (s, 1 H), 6.90-7.65 (m, 16 H).

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Example 56 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [ N '- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine

Acid 2 - {[(2R) -2-amino-2- (4-hydroxyphenyl) ethanoyl] -amino} ethanesulfonic acid (Method 80; 32.5 mg, 0.119 mmol) was mixed with DMF (4 ml) and N-methylmorpholine (30 µL, 0.272 mmol). Be obtained a clear solution, and were added successively 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 22; 50 mg, 0.099 mmol) and TBTU (38 mg, 0.119 mmol). The reaction was stirred at room temperature for 30 minutes, and was removed the DMF. The crude product was purified by HPLC preparative, using a MeCN / ammonium acetate buffer (1: 1). Lyophilization gave 55 mg of the title compound (71%). NMR (500 MHz, MeOD) 0.78-0.86 (m, 6H), 1.0-1.3 (m, 8H), 1.4-1.6 (m, 4H), 2.15 (s, 3H), 2.85-3.00 (m, 2H), 3.25 (s, 2H), 3.55-3.68 (m, 2H), 3.75 (br s, 2H), 4.65 (ABq, 2H), 5.36 (s, 1H), 6.70 (s, 1H), 6.75 (d, 2H), 6.98 (t, 1H), 7.12 (d, 2H), 7.22 (d, 2H) 7.28 (t, 2H), 7.4 (s, 1H); m / z 762.

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Examples 57-58

The following compounds were synthesized by the procedure of Example 56, using the material of appropriate departure, except that the reaction was allowed to proceed for 64 hours (Example 57) or 2 hours (Example 58), and the product was purified by preparative HPLC, using a gradient of MeCN / ammonium acetate buffer (45/55 to 60/40) as eluent.

fifty

Example 59 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) - α- [ N '- (2-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) -? -Carboxybenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro -1,5-benzothiazepine (Example 38; 66.8 mg, 0.109 mmol) and β-alanine ethyl ester hydrochloride (23.0 mg, 0.15 mmol) was dissolved in DCM (2.5 ml ), and N- methylmorpholine (0.07 ml, 0.64 mmol) was added. After stirring at room temperature for 5 minutes, TBTU (45.6 mg, 0.142 mmol) was added followed by stirring for 2 hours. The reaction mixture was filtered through a short column, and concentrated. The crude ester was dissolved in THF (1.5 ml) and water (1.5 ml), and sodium hydroxide (1 M, 0.20 mmol) was added. After stirring at room temperature for 1 hour, the reaction was paralyzed with 1 M hydrochloric acid. The reaction mixture was diluted with water (10 ml), and extracted with DCM (3 x 5 ml). The organic layers were concentrated and purified by preparative HPLC, to give the title compound (60 mg, 81%). NMR (300 MHz) 0.80 (m, 6H), 1.00-1.70 (m, 8H), 2.17 (s, 3H), 2.48 (m, 2H), 3.17 (ABq , 2H), 3.35 (m, 1H), 3.57 (m, 1H), 3.70 (m, 2H), 4.62 (ABq, 2H), 5.77 (d, 1H), 6 , 64 (s, 1H), 6.98 (t, 1H), 7.06 (d, 2H), 7.28 (m, 4H), 7.42 (m, 3H), 7.56 (m, 1H), 8.10 (m, 1H).

Examples 60-63

The following compounds were synthesized by the procedure of Example 59, using the material of appropriate game

52

53

Example 64 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) -? -Carboxy-4-methoxybenzyl) carbamoylmethoxy] -2,3,4, 5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- { N - [(R) -? - ( t -butoxycarbonyl) -4-hydroxybenzyl] -carbamo-
ilmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 78; 48 mg, 0.070 mmol), bromoethyl bromide (trimethylammonium) (57 mg, 0.230 mmol), tetrabutylammonium bromide (3 mg, 0.009 mmol) and Cs 2 CO 3 (71 mg, 0.22 mmol) to CH 3 CN (1.0 ml), and the reaction mixture was heated at reflux overnight. The solvent was evaporated, and the residue was added to water (10 ml), extracted with DCM (3 x 5 ml), and dried (MgSO 4). The crude ester was dissolved in DCM (2.5 ml), TFA (0.3 ml) was added, and the reaction mixture was stirred at room temperature overnight. The solvents were evaporated, and the crude product was purified with preparative HPLC to give the title compound (23 mg, 51%). NMR (DMSO-d 6) 0.74 (m, 6H), 0.94-1.60 (m, 8H), 2.17 (s, 3H), 3.25 (m, 2H), 3 , 69 (s, 3H), 4.70 (ABq, 2H), 4.95 (br s, 1H), 6.71 (s, 1H), 6.83 (m, 3H), 6.97 (d , 2H), 7.20 (m, 4H), 7.27 (s, 1H), 8.37 (br s, 1H).

Example 65 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N {(? - [ N '- (2-sulfoethyl) carbamoyl] -? -Methylbenzyl) ammonium salt -carba-moylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - (? -Carboxy-? -Methylbenzyl) carbamoylmethoxy] -2,3,4,5-te was dissolved -
trahydro-1,5-benzothiazepine (Example 18; 27 mg, 0.041 mmol) in DCM (2 ml). Taurine tetrabutylammonium salt (45 mg, 0.123 mmol) and TBTU (16 mg, 0.050 mmol) were successively added, and the mixture was stirred for 5 hours at room temperature. The solvent was evaporated, and the product was purified by preparative HPLC, using MeCN / ammonium acetate buffer (50/50) as eluent. Lyophilization gave the title compound with a yield of 62% (20 mg). NMR showed that 16% of the product remained as tetrabutylammonium salt. NMR (500 MHz) 0.75-0.9 (m, 6H), 1.0-1.3 (m, 8H), 1.3-1.6 (m, 4H), 1.95 (s, 3H), 2.1 (s, 3H), 2.9 (br s, 2H), 3.05 (br s, 2H), 3.55 (ABd, 2H), 3.75 (br s, 2H) , 4.55 (ABq, 2H), 6.6 (s, 1H), 6.9-7.6 (m, 12H), 8.2-8.3 (br s, 1H); m / z 777 (M + NH4 +).

Examples 66-67

The following compounds were synthesized by the procedure of Example 65, using the material of appropriate game

54

Example 68 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {α- [ N '- (carboxymethyl) carbamoyl] -? -Methylbenzyl} carbamoylmethoxy) -2,3 4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - (? - [ N '- (methoxycarbonylmethyl) carbamoyl] -? -Methyl-benzyl}) was dissolved
carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 44; 20 mg, 0.028 mmol) in 2.5 ml of a THF / water mixture (4/1). Lithium hydroxide (2 mg, 0.084 mmol) was added, and the mixture was stirred for 1 hour at room temperature. The title compound was purified by preparative HPLC, using MeCN / ammonium acetate buffer (50/50) as eluent. The MeCN was evaporated, and the remaining buffer was acidified with acetic acid. Lyophilization gave 10 mg of the product (51%). NMR 0.7-0.9 (m, 6H), 1.0-1.35 (m, 8H), 1.35-1.6 (m, 4H), 2.0 (s, 3H), 2 , 2 (s, 3H), 3.2 (br s, 2H), 3.65-3.85 (br s, 2H), 3.9-4.1 (d, 2H), 4.5-4 , 7 (ABq, 2H), 6.6 (s, 1H), 6.8 (br s, 1H), 6.9-7.5 (m, 11H), 8.1 (s, 1H); m / z 727 (M + NH4 +).

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Example 69 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {α- [ N '- (2-sulfoethyl) carbamoyl] -2-fluorobenzyl} carbamoylmethoxy) -2, 3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- { N - [α-carboxy-2-fluorobenzyl] carbamoylmethoxy} -2,3,4,5-tetrahydro- 1,5-benzothiazepine (Example 15; 20 mg, 0.030 mmol), the tetrabutylammonium salt of taurine (20 mg, 0.054 mmol) and DIPEA (25 mg, 0.19 mmol) in DMF (0.4 ml). TBTU (15 mg, 0.047 mmol) was added, and the mixture was stirred for 30 minutes at room temperature. The product was separated from the reaction mixture by preparative HPLC, using MeCN / ammonium acetate buffer (50:50) as eluent. 7 mg (29%) of the title compound were obtained. M / z = 764.5.

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Example 70 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - (R) - {α - [( N '- (R) - {α- [ N '' - (carboxymethyl) carbamoyl] benzyl} carbamoyl) -methylcarbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [ N ' - (carboxymethyl) carbamoyl] methyl} -carbamoil-
methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 43; 35 mg, 0.050 mmol) and (R) -? - [ N - ( t -butoxycarbonylme-
til) carbamoyl] benzylamine (Method 86; 20 mg, 0.076 mmol) was dissolved in DCM (2 ml), and 2,6-lutidine (0.03 ml, 0.26 mmol) was added. After stirring at room temperature for 5 minutes, TBTU (20 mg, 0.062 mmol) was added, and stirring was continued for 3 hours. The reaction mixture was filtered through a column using DCM: EtOAc, 3: 1, as eluent. The t-butyl ester was then dissolved in DCM (6 ml), and TFA (1 ml) was added. After stirring at room temperature overnight, the solvents evaporated. The toluene was added and evaporated twice. No further purification was necessary to give the title compound (40 mg, 93%). NMR (500 MHz, DMSO-d 6) 0.75 (m, 6H), 0.95-1.50 (m, 12H), 2.16 (s, 3H), 3.25 (m, 2H ), 3.75 (m, 2H), 3.90 (dd, 1H), 4.73 / 4.84 (ABq, 2H), 5.54 (m, 2H), 5.58 (d, 1H) , 6.68 (s, 1H), 6.85 (t, 1H), 6.99 (d, 2H), 7.18-7.46 (m, 13H), 8.51-8.73 (m , 4H).

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Example 71 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - (S) - (α-carboxy-4-hydroxybenzyl) carbamoylmethoxy-2,3,4,5-tetrahydro -1,5-benzothiazepine

The 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 22; 61 mg, 0.12 mmol) and the hydrochloride of (2S) -amino (4-hydroxyphenyl) acetate of methyl (31 mg, 0.14 mmol) were dissolved in DCM (4 ml), and were added 2,6-lutidine (0.04 ml, 0.34 mmol). After stirring at room temperature for 5 minutes, TBTU was added (53 mg, 0.17 mmol), and stirring was continued for 2 hours. The reaction mixture was filtered through a short column. He crude methyl ester was dissolved in THF (1.5 ml) and water (1.0 ml), and sodium hydroxide (aqueous, 1 M, 0.39 mmol) was added. Mix The reaction was stirred at room temperature for 8 hours, paralyzed with HCl (1 M), and extracted with DCM (3 x 5 ml). Layers Organic harvested were concentrated and purified with HPLC preparative, using MeCN / ammonium acetate buffer (50:50), to give the title compound (57 mg, 72%). NMR (500 MHz, CD 3 OD) 0.81 (m, 6H), 1.05-1.26 (m, 8H), 1.40-1.55 (m, 4H), 2.17 (s, 3H), 3.24 (br s, 2H), 3.74 (br s, 1H), 4.66 (ABq, 2H), 6.70-6.75 (m, 3H), 6.99 (t, 1H), 7.11 (d, 2H), 7.22-7.30 (m, 4H), 7.40 (s, 1H).

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Example 72 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - (S) - {α- [ N '- (2-sulfoethyl) carbamoyl] -4 ammonium salt -hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - (S) - (α-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5 -tetrahydro-1,5-benzothiazepine (Example 71; 31 mg, 0.047 mmol) and tetrabutylammonium taurine (57 mg, 0.155 mmol) were dissolved in DCM (2 ml). After stirring at room temperature for 5 minutes, TBTU (24 mg, 0.075 mmol) was added, and stirring was continued for 6 hours. The solvent was evaporated, and the residue was purified by preparative HPLC (twice, to remove all tetrabutylammonium salt), using MeCN / ammonium acetate buffer, to give the title compound 6 mg (16%). M / z 762.2.

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Example 73 and Example 74

1,1-Dioxo-3- (R / S) -3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - (R) - {α- [ N '- (R) - (2-imidazol-5-yl-1-carboxyethyl) carbamoyl] -benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

The 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2,3,4 , 5-tetrahydro-1,5-benzothiazepine  (Example 38; 56.4 mg, 0.092 mmol) and the dihydrochloride of Methyl D-histidinate (25.2 mg, 0.104 mmol) is added to DCM (3 ml). N-methylmorpholine was added (0.05 ml, 0.41 mmol), followed by TBTU (40 mg, 0.12 mmol). The reaction mixture was stirred at 4 ° C for 1 hour 30 minutes, and at room temperature for 3 hours. More TBTU (15 mg, 0.047 mmol) and DIPEA (0.025 ml, 0.14 mmol), and the mixture of The reaction was stirred at room temperature for another 30 minutes. The solvent was evaporated, and the residue was filtered through a short column with MeOH as eluent. The crude methyl ester is dissolved in THF (1.0 ml) and water (1.0 ml), and NaOH (aqueous, 1 M, 0.15 mmol). The reaction mixture was stirred at temperature. room for 2 hours, and was paralyzed with HCl (1 M). The Solvents were evaporated, and the residue was purified with HPLC preparative, using MeCN / ammonium acetate buffer. He compound eluted as two peaks, which were supposed to be both diastereoisomers. First peak (10 mg, 14%). Second peak (16.8 mg, 24%) First peak: NMR (DMSO-d 6) 0.74 (m, 6H), 0.95-1.60 (m, 8H), 2.17 (s, 3H), 2.82 (m, 2H), 3.23 (m, 2H), 4.27 (m, 1H), 4.80 (ABq, 2H), 5.60 (d, 1H), 6.55 (br s, 1H), 6.70 (s, 1H), 6.84 (t, 1H), 6.96 (d, 2H), 7.14-7.28 (m, 6H), 7.33 (s, 1H), 7.44 (br s, 1H), 8.54 (d, 1 H), 8.60 (br s, 1 H); m / z 748.4. Second peak: NMR (DMSO-d 6) 0.74 (m, 6H), 0.95-1.60 (m, 8H), 2.17 (s, 3H), 2.92 (dABq, 2H), 3.23 (m, 2H), 4.41 (m, 1H), 4.79 (ABq, 2H), 5.60 (d, 1H), 6.70 (s, 1H), 6.78 (s, 1H), 6.84 (t, 1H), 6.96 (d, 2H), 7.16-7.34 (m, 6H), 7.40 (m, 2H), 7.55 (s, 1H), 8.55 (d, 1H), 8.71 (d, 1H); m / z 748.4.

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Example 75 1,1-Dioxo-3,3-dibutyl-5- (4-t-butylphenyl) -7-methylthio-8- ( N - {(R) -? - [ N '- (carboxymethyl) carbamoyl] benzyl} -carbamoylmetho-xi) -2,3,4,5-tetrahydro-1,5-benzothiazepine

The title compound was isolated as a byproduct in the synthesis of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 ' - [N '- (carboxymethyl) carbamoyl] methyl} -carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine
(Example 43). Approximately 1 g of this compound was purified with preparative HPLC (MeCN / ammonium acetate buffer (50:50)) to give the title compound (32 mg). NMR (500 MHz, DMSO-d 6) 0.73 (m, 6H), 0.90-1.40 (m, 12H), 1.24 (s, 9H), 2.16 (s, 3H ), 3.23 (m, 2H), 3.65 / 3.75 (dABq, 2H), 4.72 / 4.82 (ABq, 2H), 5.60 (d, 1H), 6.65 ( s, 1H), 6.97 (d, 2H), 7.23-7.35 (m, 6H), 7.45 (d, 2H), 8.58 (d, 1H), 8.62 (t , 1 HOUR).

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Example 76 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7- ( N - ((R) -? -Carboxybenzyl) carbamoylmethylthio) -8-methoxy-2,3,4,5-tetrahydro- 1,5-benzothiazenin

The 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-carboxymethyl-thio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 81; 38 mg, 0.080 mmol) and the ester hydrochloride D-phenylglycine methyl (24 mg, 0.12 mmol) they were dissolved in DCM (2 ml), and added N-methylmorpholine (0.05 ml, 0.42 mmol). After stir at room temperature for 5 minutes, TBTU (44 mg, 0.14 mmol), and stirring was continued for 2 hours. The reaction mixture was filtered through a short column. He resulting product was dissolved in THF (1 ml) and water (1 ml), and was added sodium hydroxide (aqueous, 0.2 ml, 1 M), and the mixture of The reaction was stirred at room temperature for 2 hours. The reaction was paralyzed with HCl (1 M), diluted with water (10 ml) and extracted with DCM (3 x 3 ml). Purification with preparative HPLC produced the title compound (40 mg, 82%). NMR (DMSO-d 6) 0.75 (m, 6H), 0.96-1.60 (m, 8H), 3.22 (m, 2H), 3.56 (ABq, 2H), 3.89 (s, 3H), 4.81 (d, 1H), 6.78 (t, 1H), 6.83 (d, 2H), 6.89 (s, 1H), 7.11-7.23 (m, 7H), 7.31 (s, 1H), 8.37 (m, 1 HOUR).

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Example 77 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-carboxymethylthio-8- [ N - (? -Carboxybenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5- benzothiazepine

The 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-ethoxycarbonyl-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 82; 21 mg, 0.038 mmol) and the ester hydrochloride Phenylglycine methyl (12 mg, 0.061 mmol) dissolved in DCM (1.5 ml), and N-methylmorpholine (0.02 ml, was added 0.19 mmol). After stirring at room temperature for 5 minutes, TBTU (18 mg, 0.056 mmol) was added, and stirring was He continued for 2 hours. The reaction mixture was filtered through of a short column. The crude diester was dissolved in THF (1 ml) and water (1 ml), and sodium hydroxide (aqueous, 0.1 ml, 1 M) was added. The reaction mixture was stirred at room temperature for 2 hours, paralyzed with HCl (1 M), diluted with water (10 ml), and extracted with DCM (3 x 3 ml). The organic layers collected are concentrated and purified with preparative HPLC, using MeCN / ammonium acetate buffer (30:70 -> 40:60), to give the title compound (20 mg, 80%). NMR (CD 3 OD) 0.80 (m, 6H), 1.03-1.26 (m, 4H), 1.38-1.65 (m, 4H), 1.96 (s, 3H), 3.20 (s, 2H), 3.44 (s, 2H), 3.67 (br s, 1H), 3.76 (br s, 1H), 4.67 (ABq, 2H), 5.29 (s, 1H), 6.89 (s, 1H), 6.92 (t, 1H), 7.05 (d, 2H), 7.19-7.32 (m, 5H), 7.41 (s, 1H), 7.45 (d, 2H).

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Example 78 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - (R) - (α- { N '- [(R) - N ' - (2-hydroxy- 1-Carboxyethyl) carbamoylmethyl] carbamo-yl} -benzyl) carbamoylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [N' - (carboxymethyl) carbamoyl] methyl} -carbamoil-
methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 43; 50 mg, 0.072 mmol), the hydrochloride o- (tert-butyl) -D-serinate tert -butyl (22mg , 0.087 mmol) and N-methylmorpholine (40 mg, 0.40 mmol) were dissolved in DCM (1 ml). TBTU (29 mg, 0.090 mmol) was added, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated, and the residue was filtered through a short column (DCM: EtOAc, 1: 4). The substance obtained (approximately 60 mg) was dissolved in DCM (1 ml). TFA (0.59 g, 5.2 mmol) was added, and the mixture was stirred for 2 hours at room temperature. The solvent was evaporated, and the residue was purified by preparative HPLC, using MeCN / ammonium acetate buffer (50:50) as eluent. 38 mg (72%) of the title compound were obtained. NMR (300 MHz, DMSO-d 6) 0.7-0.8 (m, 6H), 0.9-1.5 (m, 12H), 2.2 (s, 3H), 3.2 -3.9 (m, 10H), 4.2 (br s, 1H), 4.8 (ABq, 2H), 5.6 (d, 1H), 6.7 (s, 1H), 6.8 -7.5 (m, 11H), 8.0 (d, 1H), 8.6 (d, 1H), 8.7 (t, 1H).

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Example 79 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - (R) - (α- [ N '- [(S) - N ''- (2-hydroxy -1-carboxyethyl) carbamoylmethyl] carbamo-yl} -benzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-l '- [N' - (carboxymethyl) carbamoyl] methyl} -carbamoil-
methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 43; 50 mg, 0.072 mmol), the hydrochloride of O - (tert -butyl) -L-serinate tert -butyl (22mg , 0.087 mmol) and N-methylmorpholine (40 mg, 0.40 mmol) were dissolved in DCM (1 ml). TBTU (29 mg, 0.090 mmol) was added, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated, and the residue was filtered through a short column (DCM: EtOAc, 1: 4). The substance obtained (approximately 60 mg) was dissolved in DCM (1 ml). TFA (0.44 g, 3.9 mmol) was added, and the mixture was stirred for 18 hours at room temperature. The solvent was evaporated, and the residue was purified by preparative HPLC, using MeCN / ammonium acetate buffer (50:50) as eluent. 33 mg (63%) of the title compound were obtained. NMR (300 MHz, DMSO-d 6) 0.7-0.8 (m, 6H), 0.9-1.5 (m, 12H), 2.2 (s, 3H), 3.2 -3.9 (m, 10H), 4.2 (m, 1H), 4.8 (ABq, 2H), 5.6 (d, 1H), 6.7 (s, 1H), 6.8- 7.5 (m, 11H), 7.9 (d, 1H), 8.6 (d, 1H), 8.7 (t, 1H).

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Example 80 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) - α- [ N '- (1,1-dicarboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) -? -Carboxybenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro -1,5-benzothiazepine (Example 38; 50 mg, 0.082 mmol), dimethyl aminomalonate (60 mg, 0.13 mmol) and N-methylmorpholine (55 µL, 0.5 mmol) were dissolved in DCM ( 3 ml), TBTU (42 mg, 0.13 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (95%) (2 ml), and a solution of sodium hydroxide (80 mg, 2 mmol) in water (80 µl) was added. The reaction mixture was stirred for 4 hours. The mixture was neutralized with acetic acid. The solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC, using MeCN / ammonium acetate buffer (40:60) as eluent. The collected fractions were lyophilized to obtain 4 mg (7%) of the title compound. NMR (300 MHz, CD3 OD) 0.75-0.9 (m, 6H), 1.0-1.3 (m, 4H), 1.4-1.65 (m, 4H), 2.15 (s, 3H), 3.25 (s, 2H), 3.7 (br s, 2H), 4.65-4.8 (m, 2H), 5.75 (s, 1H), 6.75 (s, 1 H), 6.9-7.55 (m, 11 H).

Examples 81-87

The following compounds were synthesized by the procedure of Example 80, using the material of appropriate heading, except that the 2,6-lutidine instead of the N-methylmorpholine, and the eluent ratio was MeCN / ammonium acetate buffer (45:55). The reaction time in Each stage varied slightly.

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Example 88 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - (S) - (α-carboxybenzyl) carbamoylmethoxyl-2,3,4,5-tetrahydro-1,5 -benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - (S) - (α-methoxycarbonylbenzyl) carbamoylmethoxy] -2,3,4,5-tetrahyde
Dro-1,5-benzothiazepine (Method 87; 55.2 mg, 0.064 mmol) was dissolved in THF (2 ml) and water (0.5 ml). Lithium hydroxide (3.1 mg, 0.127 mmol) was added, and the mixture was stirred for 1 hour. Water (1 ml) was added, and the mixture was acidified with 0.1M HCl, and extracted with DCM (3 x 2 ml). The DCM phase was dried and concentrated. The solid product was coevaporated with diethyl ether, and dissolved in HPLC grade water. Lyophilization gave the title compound as a white solid, with a yield of 68% (28 mg). NMR 0.77-0.85 (m, 6H), 1.03-1.25 (m, 8H), 1.34-1.57 (m, 4H), 2.16 (s, 3H), 3 , 18 (br s, 2H), 3.75 (br s, 2H), 4.65 (ABq, 2H), 5.7 (d, 1H), 6.63 (s, 1H), 7.0 ( t, 1H), 7.1 (d, 2H), 7.26-7.48 (m, 8H), 7.85 (d, 1H); m / z 639.

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Example 89 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - {(S) -? - [ N '- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxyl-2,3, 4,5-tetrahydro-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - {(S) -? - [ N '- (methoxycarbonylmethyl) carbamoyl] benzyl} -carbamoyl-
methoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 88; 19 mg, 0.027 mmol) was hydrolyzed with lithium hydroxide (1.3 mg, 0.054 mmol) in THF (1 ml) and water (0.3 ml). After 1 hour, water (3 ml) was added, and the mixture was acidified with 0.1M HCl and extracted with DCM (3 x 3 ml). The organic layer was dried and evaporated yielding 16 mg (82% yield) of the title compound. NMR 0.77-0.85 (m, 6H), 1.0-1.3 (m, 8H), 1.34-1.57 (m, 4H), 2.17 (s, 3H), 3 , 18 (s, 2H), 3.75 (br s, 2H), 3.90-4.20 (m, 2H), 4.65 (ABq, 2H), 5.87 (m, 1H), 6 , 63 (s, 1H), 6.98-7.50 (m, 12H), 8.12-8.20 (m, 1H); m / z 696.

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Example 90 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - {(S) - α- [ N '- (2-sulfoethyl) carbamoyl] benzyl} carbamoyl sodium salt -methoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - (S) - (α-carboxybenzyl) carbamoylmethoxy] -2,3,4,5-tetranidro-1 ,5-
Benzothiazepine (Example 88; 41 mg, 0.064 mmol) was dissolved in 3 ml of DCM. Taurine tetrabutylammonium salt (70 mg, 0.191 mmol) and TBTU (25 mg, 0.078 mmol) were successively added, and the mixture was stirred overnight at room temperature. The solvent was evaporated, and the product was purified by preparative HPLC, using a gradient of MeCN / ammonium acetate buffer (45/55 to 55/45) as eluent. Lyophilization of the collected fractions, and then ion exchange chromatography on 4 g of Amberlite CG 120, Na + form, gave the title compound in 85% yield (42 mg). NMR 0.7-0.8 (m, 6H), 0.9-1.2 (m, 8H), 1.3-1.5 (m, 4H), 2.0 (s, 3H), 2 , 9-3.2 (m, 2H + 2H), 3.3-3.8 (m, 2H + 2H), 4.4-4.7 (m, 2H), 5.6 (m, 1H) , 6.57 (s, 1H), 6.9-7.5 (m, 11H), 7.8-8.1 (m, 2H); m / z 746.

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Example 91

The following compound was synthesized by procedure of Example 90, using the starting material appropriate, except that the product was purified using a gradient buffer 40/60 to 70/30, and then lyophilized to give the salt of ammonium.

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Example 92 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7- [ N - {(R) -? - [ N '- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy] -2, sodium salt 3,4,5-tetrahydro-1,5-benzothiazepine

The sodium salt of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 01/66533; 120 mg, 0.278 mmol), dissolved in DCM (4 ml), was added to a solution of α- [ N - ( t -butoxycarbonylmethyl) carbamoyl] benzylamine (Method 86; 90%, 150 mg, 0.511 mmol) in DCM (3 ml). 2,6-Dimethylpyridine (65 µL, 0.559 mmol) and TBTU (137 mg, 0.427 mmol) were added, and the reaction mixture was stirred at room temperature overnight. The solution was filtered using DCM / EtOAc (8/2) as eluent. The solvent was evaporated. DCM (4 ml) and TFA (0.6 ml) were added, and the mixture was stirred overnight. The solvent was evaporated, and the crude product was purified by preparative HPLC on a Chromasil C 18 column. A gradient of MeCN / ammonium acetate buffer (50/50 to 100/0) was used as the mobile phase. The MeCN was evaporated, and lyophilization gave the title compound in a yield of 36% (62 mg). NMR 0.73-0.82 (m, 6H), 1.00-1.23 (m, 4H), 1.30-1.65 (m, 4H), 3.05-3.18 (m, 2H), 3.65 (br s, 2H), 3.75 (ABdd, 2H), 4.46 (ABq, 2H), 5.70 (d, 1H), 6.79-7.24 (m, 10H), 7.36 (d, 2H), 7.46 (d, 1H), 7.83 (d, 1H), 8.00 (br s, 1H); m / z 622.

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Example 93-94

The following compounds were synthesized by the procedure of Example 92, using the material of appropriate heading, except that HPLC chromatography was performed on a column of Chromasil C 8, and the gradient of the eluent It was 45/55 to 60/40.

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Example 95 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- { N - [(R) - α- ( N '- {2 - [(ethoxy) (methyl) phosphoryl ] ethyl} carbamoyl) benzyl] -carba-moylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 2 - [(methyl) (ethyl) phosphoryl] -ethylamine (Helv. Chim. Acta; GE; 75; 8; 1992; 2545-2552; 16 mg, 0.106 mmol) in DCM (2 ml) was added , at 0 ° C, 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2 , 3,4,5-tetrahydro-1,5-benzothiazepine (Example 38; 50 mg, 0.082 mmol), DIPEA (42 mg, 0.328 mmol) and TBTU (34 mg, 0.106 mmol), under an argon atmosphere. The reaction mixture was stirred at room temperature for 110 minutes, and then DCM was added and the solution was washed with NaHCO3 (aqueous, saturated) and brine. The organic layer was dried, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography, and the product eluted with DCM / methanol (100: 5). Yield 43 mg (71%). NMR (500 MHz) 0.78-0.85 (m, 6 H), 1.02-1.54 (m, 12H), 1.6-1.75 (br, 1H), 1.8-2 , 10 (m, 3H), 2.21 (s, 3H), 3.10-3.25 (m, 2H), 3.51-3.84 (m, 4 H), 3.9-3, 99 (m, 1H), 4.01-4.09 (m, 1H), 4.54-4.69 (dd, 2H), 5.51 (d, 1H), 6.68 (s, 1H) , 6.96-7.02 (m, 1H), 7.03-7.18 (m, 3H), 7.25-7.42 (m, 6H), 7.43-7.48 (m, 2H), 8.05-8.15 (m, 1H).

Examples 96-97

The following compounds were synthesized by the procedure of Example 95, using the material of appropriate game

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Example 98 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- { N - [(R) - α- ( N '- {2 - [(hydroxy) (methyl) phosphoryl ] ethyl} carbamoyl) benzyl] -carba-moylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- { N - [(R) -? - ( N '- {2 - [(ethoxy) (methyl) phosphoryl] -ethyl}
carbamoyl) benzyl] carbamoylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 95; 27 mg, 0.036 mmol) in ethanol (1.5 ml) was added, at 0 ° C, aqueous sodium hydroxide 2M (0.22 ml, 0.44 mmol). The reaction mixture was stirred at room temperature for 24 hours. Acetic acid (0.2 ml) was added. The solvent was evaporated under reduced pressure, and the residue was extracted with DCM / water. The DCM layer was separated, washed with brine, dried and evaporated under reduced pressure. Recrystallization of the residue from DCM / ether / petroleum ether gave 23 mg of the title compound (89%). NMR (600 MHz) 0.74-0.82 (m, 6H), 1.0-1.70 (m, 11H), 1.90-2.09 (m, 2H), 2.16 (s, 3H), 3.05-3.24 (m, 2H), 3.40-3.85 (m, 4H), 4.50-4.65 (dd, 2H), 5.55 (d, 1H) , 6.63 (s, 1H), 6.93-7.07 (m, 3H), 7.20-7.50 (m, 9H), 8.10 (d, 1H); m / z 716.3.

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Example 99 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) - α- [ N '- [(hydroxy) (ethoxy) phosphorylmethyl] carbamoyl} benzyl) -carba-moylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) -? - { N '- [(diethoxy) phosphorylmethyl] - carbamo-
il} benzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 96; 13 mg, 0.017 mmol) in MeCN (0.5 ml) 1M aqueous LiOH (0.171) was added dropwise ml, 0.171 mmol). The reaction mixture was stirred at room temperature for 3 days. Acetic acid was added, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC, using MeCN and ammonium acetate buffer (45:55) as eluent, to give 11 mg of the title compound (88%). NMR (600 MHz, CD 3 OD 0.77-0.84 (m, 6H), 1.00-1.30 (m, 7H), 1.40-1.65 (m, 4H), 2 , 17 (s, 3H), 3.23 (br s, 2H), 3.51 (d, 2H), 3.6-3.85 (m, 4H), 4.70 (dd, 2H), 5 , 57 (s, 1H), 6.72 (s, 1H), 6.96 (t, 1H), 7.09 (d, 2H), 7.25-7.31 (m, 3H), 7, 32-7.36 (m, 2H), 7.40 (s, 1H), 7.45 (d, 2H); m / z 732.4.

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Example 100 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) - α- { N '- [(hydroxy) (methyl) phosphorylmethyl] carbamoyl} benzyl) -carba-moylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) -? - ( N '- [(ethoxy) (methyl) phosphorylmethyl] -car-
bamoyl} benzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 97; 85 mg, 0.12 mmol) in MeCN (2.4 ml) was added dropwise, at 0 ° C , 1M aqueous LiOH (1.17 ml, 1.17 mmol). The reaction mixture was stirred at room temperature for 20 hours. Acetic acid was added, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography, using DCM / Methanol / Et3N (100: 15: 0.2 and 100: 30: 0.2) as eluent, to give 62 mg of the title compound (76 %). NMR (CD 3 OD) 0.75-0.84 (m, 6H), 1.0-1.70 (m, 11H), 2.15 (s, 3H), 3.22 (br s, 2H), 3.35 (d, 2H), 3.60-3.90 (m, 2H), 4.70 (dd, 2H), 3.55 (s, 1H), 6.71 (s, 1H ), 6.96 (t, 1H), 7.09 (d, 2H), 7.23-7.38 (m, 5H), 7.40 (s, 1H), 7.46 (d, 2H) ; m / z 702.3.

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Example 101

The following compound was synthesized by procedure of Example 100, using the starting material appropriate.

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Example 102 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) - α- { N '- [di- ( t -butyloxy) phosphorylmethyl] carbamoyl } benzyl) -carbamoyl-methoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoyl-methoxy] -2,3,4,5-tetranidro-1,5-benzothiazepine (Example 38; 80 mg, 0.131 mmol) and di- ( t -butyloxy) phosphorylmethylamine (Tet. Lett .; EN; 33; 1; 1992; 77 -80; 37 mg, 0.164 mmol) in DCM (5 mL) 2,6-lutidine (28 mg, 0.262 mmol) and TBTU (53 mg, 0.164 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours and 50 minutes. The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography, using DCM / Methanol (100: 4) as eluent, to give 92 mg of the title compound (86%). NMR (500 MHz) 0.77-0.86 (m, 6H), 1.03-1.75 (m, 26H), 2.22 (s, 3H), 2.10-2.25 (m, 2H), 3.45-3.90 (m, 4H), 4.61 (dd, 2H), 5.52 (d, 1H), 5.94 (br s, 1H), 6.67 (s, 1H), 7.0 (t, 1H), 7.07 (d, 2H), 7.26-7.48 (m, 8H), 8.12 (d, 1H); m / z 704.22 [M-2 ( t -butyl) + 2H].

Example 103 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) - α- { N '- [di- (hydroxy) phosphorylmethyl] carbamoyl} benzyl ) -carbamoyl-methoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) - α- { N '- [di- ( t -butoxy ) phosphorylmethyl] -carbamoyl} benzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 102; 72 mg, 0.088 mmol) in DCM (4 ml) was added, at 0 ° C, TFA ( 1 ml) The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was extracted with DCM / water. The organic layer was separated, washed with brine, dried, and evaporated under reduced pressure. The residue was suspended in ether, and the crystals were filtered to give 60 mg of the title compound (97%). NMR (500 MHz, DMSO-d6) 0.70-0.80 (m, 6H), 0.99-1.61 (m, 8H), 2.18 (s, 3H), 2.80 -4.0 (m, 6H), 4.80 (dd, 2H), 5.65 (d, 1H), 6.71 (s, 1H), 6.80-7.02 (m, 3H), 7.15-7.35 (m, 6H), 7.48 (d, 2H), 8.50-9.20 (m, 2H); m / z 704.3.

Example 104 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- { N - [(R) -? - ( N '- {2 - [(methyl) (ethyl) phosphoryl] ethyl } carbamoyl) benzyl] -carbamoyl-methoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoyl-methoxy] -2 , 3,4,5-tetrahydro-1,5-benzothiazepine (Example 1; 60 mg, 0.094 mmol) and 2 - [(methyl) (ethyl) phosphoryl] ethylamine (Helv. Chim. Acta; GE; 75; 8; 1992; 2545-2552; 20 mg, 0.132 mmol), at 0 ° C, 2,6-lutidine (20 mg, 0.19 mmol) and TBTU (39 mg, 0.121 mmol) were added under argon. The reaction mixture was stirred at room temperature for 70 minutes, and then DCM was added and the solution was washed with water and brine. The organic layer was dried, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography, using DCM / MeOH (100: 5) as eluent, to give 67 mg of the title compound (92%). NMR (300 MHz) 0.74-86 (m, 6H), 1.0-1.60 (m, 18H), 1.80-2.05 (m, 2H), 2.20 (s, 3H) , 2.17 (s, 2H), 3.47-3.80 (m, 4H), 3.88-4.10 (dd, 2H), 5.52 (d, 1H), 6.65 (s , 1H), 6.95-7.12 (m, 3H), 7.13-7.42 (m, 7H), 7.43-7.49 (m, 2H), 8.05-8.16 (m, 1 H); m / z 772.4.

Example 105

To a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - ((R) - α- { N '- [2- (triphenylmethylsulfanyl) -1- ( t -butoxi-
carbonyl) ethyl] carbamoyl} benzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 91; 37 mg, 0.036
mmoles) in DCM (1 ml) TFA (1 ml) was added at 0 ° C, in an argon mantle. The ice bath was removed, and triethylsilane (42 mg, 0.36 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC, using MeCN and ammonium acetate buffer (40:60 to 60:40) as eluent, to give 16 mg of the title compound (59%). NMR (500 MHz, CD 3 OD) 0.76-0.85 (m, 6H), 1.05-1.60 (m, 12H), 2.17 (s, 3H), 2.77- 2.92 (m, 2H), 3.24 (br s, 2H), 3.61-3.88 (m, 2H), 4.56 (t, 1H), 4.70 (dd, 2H), 5.65 (s, 1H), 6.71 (s, 1H), 6.98 (t, 1H), 7.12 (d, 2H), 7.25-7.43 (m, 6H), 7 , 50 (d, 2H); m / z 742.4.

Example 106

The following compound was synthesized by procedure of Example 105, using the starting material appropriate.

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Example 107 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- (2- { N - [(R) - α- (carboxy) benzyl] carbamoyl} ethoxy) -2, 3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- (2- {N - [(R) -? - ( t -butoxycarbonyl) benzyl] -carbamoyl} ethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 90; 77 mg, 0.108 mmol) in DCM (3 ml) TFA (0.75 ml) was added at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours and 45 minutes. The solvent was evaporated under reduced pressure, and the crude product was purified by preparative HPLC, using MeCN and ammonium acetate buffer (40:60 to 50:50) as eluent, to give 60 mg of the title compound (82%) . NMR (500MHz, CD3 OD) 0.75-0.85 (m, 6H), 1.0-1.25 (m, 4H), 1.40-1.64 (m, 4H), 2 , 75-2.90 (m, 2H), 3.26 (s, 2H), 3.50-3.90 (m, 2H), 4.30-4.41 (m, 2H), 5.43 (s, 1H), 6.99 (t, 1H), 7.05-7.13 (m, 3H), 7.23-7.34 (m, 5H), 7.45 (d, 2H), 7.52 (s, 1 H); m / z 658.

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Example 108

The following compound was synthesized by procedure of Example 107, using the starting material appropriate.

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Example 109 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- { N - [(R) -? - ( N '- {2 - [(methyl) (ethyl) phosphoryl] ethyl } carbamoyl) -4-hydroxybenzyl] carbamoylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - ((R) -? -Carboxy-4-hydroxybenzyl) carbamoyl-methoxy] -2, 3,4,5-tetrahydro-1,5-benzothiazepine (Example 2; 80 mg, 0.122 mmol) and 2 - [(methyl) (ethyl) phosphoryl] ethylamine
(Helv. Chim. Acta; GE; 75; 8; 1992; 2545-2552; 24 mg, 0.159 mmol) in DCM (2 mL) 2,6-lutidine (26 mg, 0.244 mmol) and TBTU (51 mg , 0.159 mmol), under argon. The reaction mixture was stirred at room temperature for 60 minutes, then diluted with DCM. The solution was washed with water, with brine, dried and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using DCM / MeOH (100: 7) as eluent, to give 67 mg of the title compound (92%). NMR (600 MHz), 0.74-0.80 (m, 6H), 1.0-1.55 (m, 18H), 1.82-1-98 (m, 2H), 2.15 (s , 3H), 3.14 (br s, 2H), 3.40-3.56 (m, 2H), 3.70 (br s, 2H), 3.89-4.02 (m, 2H), 4.51 (dd, 2H), 5.33 (t, 1H), 6.61 (s, 1H), 6.65-6.72 (m, 2H), 6.95 (t, 1H), 7 , 03 (d, 2H), 7.12-7.19 (m, 3H), 7.22-7.26 (m, 2H), 7.32 (s, 1H), 8.11 (t, 1H ); m / z 788.56.

Example 110 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- { N - [(R) -? - ( N '- {2 - [(methyl) (hydroxy) phosphoryl] ethyl } carbamoyl) -4-hydroxybenzyl] carbamoylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- { N - [(R) -? - ( N '- {2 - [(methyl) (ethyl) ) phosphoryl] ethyl} -carba-
moyl) -4-hydroxybenzyl] carbamoylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 104; 37 mg, 0.047 mmol) in MeCN / MeOH (4 ml, 1: 1) LiOH was added 1 M aqueous (0.8 ml, 0.8 mmol). The reaction mixture was stirred at room temperature for 40 minutes. Acetic acid was added, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC using MeCN and ammonium acetate buffer (40:60 and 45:55) as eluent, to give 35 mg of the title compound (96%). NMR (500 MHz, CD3 OD) 0.78-0.85 (m, 6H), 1.06-1.28 (m, 11H), 1.39-1.57 (m, 4H), 1.72-1.85 (m, 2H), 2.16 (s, 3H), 2.24 (s, 2H), 3.40-3.50 (m, 2H), 3.65-3, 84 (m, 2H), 4.69 (dd, 2H), 5.36 (s, 1H), 6.71 (s, 1H), 6.76 (d, 2H), 6.99 (t, 1H ), 7.13 (d, 2H), 7.22-7.33 (m, 4H), 7.39 (s, 1H); m / z 760.27.

Example 111 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [(R) - N '- (2-methylsulfinyl-1-carboxyethyl) carbamoyl] benzyl} -carba-moylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

The title compound was separated as a by-product from the synthesis of Example 108. NMR (500 MHz, CD 3 OD) 0.78-0.85 (m, 6H), 1.02-1.60 (m, 12H), 2.16 (d, 3H), 2.53 (d, 3H), 3.08-3.18 (m, 1H), 3.24 (s, 2H), 3.35 (v br, 1H), 3.75 (v br, 2H), 4.62 (v br, 1H), 4.71 (dd, 2H), 5.60 (d, 1H), 7.71 (s, 1H), 6.98 (t, 1H), 7.12 (d, 2H), 7.25-7.42 (m, 6H), 7.47 (d, 2H); m / z 772.25.

Example 112 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [(S) - N '- (3-methylthio-2-carboxypropyl) carbamoyl] benzyl} -carba-moylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [(S) - N '- (3-methylthio- 2-Methoxycarbonyl-propyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 94, 68 mg, 0.087 mmol) in ethanol (5 ml) NaOH (9 mg) was added in 0.4 ml water), at 0 ° C. The reaction mixture was stirred at room temperature for 2.5 hours. Acetic acid was added, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC using MeCN and ammonium acetate buffer (40:60 to 60:40) as eluent, to give 52 mg of the title compound (76%). NMR (500 MHz, CD 3 OD) 0.79-0.86 (m, 6H), 1.05-1.29 (m, 8H), 1.40-1.58 (m, 4H), 1.84-1.93 (m, 4H), 2.01-2.21 (m, 5H), 2.26-2.34 (m, 1H), 3.26 (s, 2H), 3, 76 (br s, 2H), 4.52-4.58 (m, 1H), 4.70 (dd, 2H), 5.61 (s, 1H), 6.73 (s, 1H), 7, 0 (t, 1H), 7.14 (d, 2H), 7.27-7.43 (m, 6H), 7.49 (d, 2H); m / z 770.16.

Example 113 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [(S) - N '- (2-methylthio-1-carboxyethyl) carbamoyl] benzyl} -carbamoyl-methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [(S) - N '- (2-mercapto- 1-Carboxyethyl) -carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 106; 15 mg, 0.02 mmol) in methanol (1.5 ml) methoxide was added of sodium (0.104 mmol in 0.14 ml methanol) and methyl iodide (0.16 mmol), under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 50 minutes. Acetic acid was added. The solvent was evaporated under reduced pressure, and the residue was extracted with DCM / water. The organic layer was separated, washed with brine, dried and evaporated under reduced pressure to give 4 mg of the title compound (26%). NMR (500 MHz, CD3 OD) 0.75-8.30 (m, 6H), 1.03-1.57 (m, 12H), 2.10 (s, 3H), 2.17 ( s, 3H), 2.83-2.30 (m, 1H), 3.0-3.25 (m, 1H), 3.26 (s, 2H), 3.77 (br s, 2H), 4.58-4.63 (m, 1H), 4.72 (dd, 2H), 5.64 (s, 1H), 6.72 (s, 1H), 7.0 (t, 1H), 7 , 12 (d, 2H), 7.28-7.52 (m, 8H); m / z 756.25.

Example 114 1,1-Dioxo-3,3-dibutyl-5- (4-chlorophenyl) -7-methylthio-8- [ N - {(R) - α- [ N '- (carboxymethyl) carbamoyl] benzyl} carbamoyl- meto-xi] -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3,3-dibutyl-5- (4-chlorophenyl) -7-methylthio-8- [ N - {(R) -? - [ N '- ( t -butoxycarbonyl- methyl) carbamoyl] benzyl} carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 102; 129 mg, 0.164 mmol) in DCM (5 ml) TFA (1.5 ml) was added, at 0 ° C, under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by preparative HPLC, using MeCN and ammonium acetate buffer (40:60 to 50:50) as eluent, to give 77 mg of the title compound (63%) . NMR (500 MHz, CD3 OD) 0.84 (t, 6H), 1.10-1.22 (m, 8H), 1.35-1.45 (m, 4H), 2.34 ( s, 3H), 3.19-3.27 (m, 2H), 3.55 (s, 2H), 3.87 (dd, 2H), 4.67 (dd, 2H), 5.61 (s , 1H), 7.09-7.15 (m, 3H), 7.27-7.37 (m, 6H), 7.47 (d, 2H); m / z 748.03 (M + NH 3).

Example 115 1,1-Dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8- [ N {(R) -? - [ N '- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 118; 0.050 g, 0.105 mmol) in DMF (4 ml) 2 - {[(2 R ) -2-amino-2- (4-hydroxyphenyl) -ethanoyl] amino} ethanesulfonic acid (Method 80; 0.037 g, 0.135 mmol) and N -methylmorpholine (0.040 ml, 0.363 mmol). The mixture was stirred for 10 minutes, and then TBTU (0.044 g, 0.137 mmol) was added. The reaction mixture was stirred for two days before the solvent was removed under reduced pressure. The residue was purified by preparative HPLC, using MeCN / ammonium acetate buffer, to give the title compound with 0.042 g (55%) as a white solid. NMR (DMSO-d6) 0.60-0.80 (m, 6H), 1.05-1.50 (m, 8H), 2.15 (s, 3H), 2.45-2, 55 (m, 2H), 3.05-3.80 (m, 6H), 4.70 (ABd, 1H), 4.80 (ABd, 1H), 5.25 (d, 1H), 6.65 -6.75 (m, 3H), 6.80-7.05 (m, 3H), 7.10-7.25 (m, 4H), 7.30 (s, 1H), 8.20-8 , 30 (m, 1H), 8.45 (d, 1H).

Example 116 1,1-Dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8- [ N {(R) -? - N '- (carboxymethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmetho-xi] - 2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 118; 0.050 g, 0.105 mmol) in DCM (4 ml) (R) -? - [ N - ( t -butoxycarbonylmethyl) -carbamoyl] benzylamine (Method 86; 0.036 g, 0.136 mmol) and N-methylmorpholine (0.040 ml, 0.363 mmol) ). The mixture was stirred for 5 minutes, and then TBTU (0.044 g, 0.137 mmol) was added. The reaction mixture was stirred for two days, and then TFA (1.5 ml) was added. After 1.5 hours, the solution was diluted with toluene, before the solvent was removed under reduced pressure. The residue was purified by preparative HPLC, using MeCN / ammonium acetate buffer, to give 0.020 g of the title compound (29%) as a white solid. NMR (DMSO-d6) 0.60-0.80 (m, 6H), 1.05-1.50 (m, 8H), 2.15 (s, 3H), 3.10-3, 80 (m, 6H), 4.70 (ABd, 1H), 4.85 (ABd, 1H), 5.60 (d, 1H), 6.70 (s, 1H), 6.80-7.05 (m, 3H), 7.15-7.50 (m, 8H), 8.35 (br s, 1H), 8.55 (d, 1H).

Example 117 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8- [ N - {(R) - α- [ N '- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy ] -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 6; 0.020 g, 4.09x10 -5 mol) in DMF (4 ml) 2 - {[(2 R ) -2-amino-2- (4-hydroxyphenyl) -ethanoyl] amino} ethanesulfonic acid (Method 80; 0.014 g, 5.10x10-5 mol) and N- methylmorpholine (0.020 ml, 1.81x10-4 mol). The mixture was stirred for 10 minutes, and then TBTU (0.016 g, 4.98x10-5 mol) was added. The reaction mixture was stirred for 3 hours, and then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC, using MeCN / ammonium acetate buffer, to give 0.023 g of the title compound (75%) as a white solid. NMR (500 MHz, DMSO-d 6) 0.65-0.80 (m, 6H), 0.80-1.50 (m, 12H), 2.40-2.60 (m, 2H) , 3.15-3.45 (m, 4H), 3.60 (s, 3H), 3.65 (br s, 2H), 4.60 (ABd, 1H), 4.70 (ABd, 1H) , 5.25 (d, 1H), 6.50 (s, 1H), 6.70-7.25 (m, 10H), 7.35 (s, 1H), 8.20-8.30 (m , 1H), 8.50 (d, 1H), 9.40 (br s, 1H).

Example 118 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8- [ N - {(R) -? - [ N '- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy] - 2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 115; 0.020 g, 4, 63x10-5 mol) in DMF (4 ml) 2 - ([(2 R ) -2-amino-2- (4-hydroxyphenyl) ethanoyl] amino} -ethanesulfonic acid (Method 80; 0.017 g, 6.20x10 -5 moles) and N- methylmorpholine (0.016 ml, 1.46x10-4 moles) The mixture was stirred for 10 minutes, and then TBTU (0.019 g, 5.92x10 ^ {-5} mol.) The reaction mixture was stirred overnight, and then the solvent was removed under reduced pressure.The residue was purified by preparative HPLC, using MeCN / ammonium acetate buffer, to give 0.008 g of the compound of the title (24%) as a white solid. NMR (500 MHz, DMSO-d6) 0.65-0.80 (m, 6H), 0.80-1.60 (m, 8H), 2 , 40-2.55 (m, 2H), 3.20-3.40 (m, 4H), 3.65 (br s, 2H), 4.65 (ABd, 1H), 4.70 (ABd, 1H), 5.25 (d, 1H), 6.65-7.45 (m, 13H), 8.20-8.30 (m, 1H), 8.60 (d, 1H), 9.40 (br s, 1H).

Example 119 1,1-Dioxo-3,3-dibutyl-5- (4-t-butoxycarbonylaminophenyl) -8- [ N - (α- (R) -carboxybenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro- 1,5-benzothiazepine

The title compound was synthesized from 1,1-dioxo-3,3-dibutyl-5- (4-t-butoxycarbonylaminophenyl) -8- [ N - (α- (R) -methoxycarbonylbenzyl) carbamoylmethoxy] -2 , 3,4,5-tetrahydro-1,5-benzothiazepine (Method 45) by the method of Method 109. NMR (CD 3 OD) 0.81 (br t, 6H), 1.03-1.3 (m, 8H), 1.32-1.59 (m, 13H), 3.24 (br s, 2H), 3.57-3.77 (m, 2H), 4.61 (br s, 2H ), 5.51 (s, 1H), 6.83 (d, 1H), 7.0-7.1 (m, 3H), 7.26-7.43 (m, 7H), 7.49 ( d, 1H); m / z 708.5.

Example 120 1,1-Dioxo-3,3-dibutyl-5- [4- ( N '- t -butylureido) phenyl] -8- [ N -? - (R) -carboxybenzyl) carbamoylmethoxy] -2,3,4 , 5-tetrahydro-1,5-benzothiazepine

1,1-dioxo-3,3-dibutyl-5- (4- ( N '- t -butylureido) -phenyl) -8- [ N - (α- (R) -methoxycarbonylbenzyl) carbamoylmethoxy] -2, 3.4,
5-tetrahydro-1,5-benzothiazepine (Method 111; 30 mg, 0.042 mmol) was dissolved in THF (1.5 ml), water (0.5 ml) and LiOH (42 mg, 0.064 mmol, monohydrate) was added . The mixture was stirred for 2 hours. The compound was purified by preparative HPLC, using a gradient of MeCN / ammonium acetate buffer (5/95 to 100/0) as eluent, to give 24 mg of the title compound, (82%). NMR (CD 3 OD) 0.81 (br t, 6H), 1.05-1.26 (m, 8H), 1.35 (s, 9H), 1.38-1.57 (m, 4H), 3.25 (br s, 2H), 3.6-3.77 (m, 2H), 4.61 (ABq, 2H), 5.45 (s, 1H), 6.84 (d, 1H), 7.01-7.11 (m, 3H), 7.24 (d, 2H), 7.26-7.37 (m, 3H), 7.37-7.42 (m, 2H) , 7.50 (d, 1 H); m / z 707.5.

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Preparation of starting materials

The starting materials for the Examples Above are commercially available, or are prepared easily using standard methods from materials known. For example, the following reactions are a illustration, but not a limitation, of some of the materials of heading used in the previous reactions.

Method one

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [1 '- (ethoxycarbonyl) ethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine

Sodium carbonate (0.30 g, 2.83 was added mmoles), 2-bromopropanoic acid ethyl ester (0.145 g, 0.796 mmol) and tetrabutylammonium bromide (0.022 g, 0.07 mmol) at a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (WO 96/16051; 0.300 g, 0.663 mmol) in MeCN (10 ml). The suspension was heated to reflux overnight. The solvent is evaporated, and the crude mixture was extracted with (DCM / H2O), dried (MgSO 4), evaporated and purified by chromatography snapshot (Hex: EtOAc - 5: 1), to give 0.346 g of the compound of title (95%) as a white solid. NMR 0.70-0.85 (m, 6H), 1.00-1.75 (m, 8H), 1.35 (t, 3H), 1.70 (d, 3H), 3.05-3.25 (m, 2H), 3.55-3.90 (m, 2H), 4.20-4.35 (m, 2H), 4.80 (q, 1H), 7.00-7.10 (m, 3H), 7.15 (s, 1H), 7.25-7.35 (m, 2H), 7.45 (s, 1H).

Method 2

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [1'-carboxyethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

Sodium hydroxide (0.045 g, 1.13 was added mmoles) to a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [1- (ethoxycarbonyl) ethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 1; 0.050 g, 0.090 mmol) in EtOH (4 ml, 95%), and heated at reflux. After 1.5 hours, AcOH (0.2 ml) was added, and the Most of the solvent was removed under reduced pressure. He crude product was extracted with (DCM / H2O), dried (MgSO4) and evaporated to give 0.031 g of the title compound (65%) as a white solid NMR (500 MHz, CD 3 OD) 0.70-0.85 (m, 6H), 0.95-1.25 (m, 4H), 1.35-1.70 (m, 4H), 2.65 (d, 3H), 3.10-3.35 (m, 2H), 3.45-3.95 (m, 2H), 4.70 (q, 1H), 6.90-7.35 (m, 6H), 7.45 (s, 1 HOUR).

Method 3

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [1'-phenyl-1'-ethoxycarbonylmethoxyl-2,3,4,5-tetrahydro-1,5-benzothiazepine

They were added ethyl α-bromophenylacetate (0.139 g), Na 2 CO 3 (0.200 g) and tetrabutylammonium bromide (0.034 g) to a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (WO 96/16051; 0.200 g, 0.442 mmol) in MeCN (6 ml). The suspension was heated to reflux all night before the Solvent will be removed under reduced pressure. The gross product is extracted with (DCM / H2O), and purified by chromatography ultrafast (Hex: EtOAc - 5: 1) to give 0.256 g of the compound of title (94%) as a white solid. NMR 0.65-0.85 (m, 6H), 0.95-1.65 (m, 8H), 3.00-3.15 (m, 2H), 3.50-3.80 (m, 2H), 3.70-3.80 (2s, 3H), 5.60 (s, 1H), 5.65 (d, 1H) 7.00-7.60 (m, 17H), 8.05-8.20 (2d, 1 HOUR).

Method 4

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [1'-phenyl-1'-carboxymethoxy] -2,3,4,5-tetrahydro-1,5- benzothiazepine

Lithium hydroxide (0.019 g) was added to a dissolution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [1'-phenyl-1'-ethoxycarbonylmethoxy] -2,3,4,5-tetrahydro-1,5- benzothiazepine  (Method 3; 0.244 g, 0.397 mmol) in THF / H2O (2/1, 3 ml). After 2 days, the solvent was removed under reduced pressure, and The crude mixture was purified by HPLC to give 0.215 g of title compound (92%) as a white solid. NMR (CD 3 OD) 0.60-0.80 (m, 6H), 0.90-1.25 (m, 4H), 1.30-1.60 (m, 4H), 3.05-3.30 (m, 2H), 3.40-3.90 (m, 2H), 5.55 (s, 1H), 6.85-7.70 (m, 12H).

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Method 5

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-ethoxycarbonyl-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

Ethyl bromoacetate (0.13 ml) was added, Na 2 CO 3 (0.40 g) and tetrabutylammonium bromide (0.030 g) at a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (synthesized as described in WO9616051 for the analogue of 3-butyl-3-ethyl correspondent; 0.400 g, 0.927 mmol) in MeCN (10 ml). The suspension was heated to reflux all night before the major part of the solvent will be removed under reduced pressure. The product crude was extracted with (DCM / H2O), and filtered through a short silica column (DCM: EtOAc - 1: 4) to give 0.476 g of title compound (99%). NMR 0.65-0.85 (m, 6H), 0.95-1.65 (m, 8H), 3.00-3.15 (m, 2H), 3.50-3.80 (m, 2H), 3.70-3.80 (s, 3H), 5.60 (s, 1H), 5.65 (d, 1H) 7.00-7.60 (m, 17H), 8.05-8.20 (d, 1H).

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Method 6

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-carboxymethoxy-2,3,4,5-tetrahydro-l, 5-benzothiazepine

Lithium hydroxide (0.062 g) was added to a dissolution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 5; 0.448 g, 0.865 mmol) in THF / H2O (2/1, 6 ml). After 1 hour, AcOH (0.5 ml) was added, and most of the Solvent was removed under reduced pressure. The gross product is purified by HPLC (MeCN) to give the title compound 0.408 g (96%) as a white solid. NMR (CD 3 OD) 0.75-0.85 (m, 6H), 1.00-1.30 (m, 8H), 1.35-1.55 (m, 4H), 3.20 (s, 2H), 3.65 (s, 3H), 3.70 (br s, 2H), 4.50 (s, 2H), 6.50 (s, 1H), 6.90-7.30 (m, 5H), 7.40 (s, 1H).

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Method 7

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

They got hot 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 9616051; 1.0 g), ethyl bromoacetate (0.50 g), sodium carbonate (1.2 g) and tetrabutylammonium bromide (60 mg) in MeCN (15 ml) at reflux overnight. The solvent was removed at reduced pressure, and the residue was extracted with (DCM / H2O). The organic layer was separated, and the solvent was removed under pressure reduced The residue was purified by chromatography (DCM / EtOAc (90:10)) to give 1.2 g of the title compound (98%). NMR (CD 3 OD) 0.75-0.85 (m, 6H), 1.00-1.30 (m, 8H), 1.35-1.55 (m, 4H), 3.20 (s, 2H), 3.65 (s, 3H), 3.70 (br s, 2H), 4.50 (s, 2H), 6.50 (s, 1H), 6.90-7.30 (m, 5H), 7.40 (s, 1H).

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Method 8

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

A mixture of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (docu-
WO 96/16051; 0.3 g), ethyl bromoacetate (0.14 g), sodium carbonate (0.3 g), tetrabutylammonium bromide (0.02 g) in MeCN (10 ml) was heated at reflux for 4 hours. The solvent was removed under reduced pressure. The residue was partitioned between DCM / H2O, and the organic layer was separated. The solvent was evaporated, and the residue was purified by chromatography (DCM / Et0Ac, 90:10) to give 0.34 g of the title compound (95%). NMR (500 MHz) 0.7-0.9 (m, 6H), 1.0-1.8 (m, 11H), 3.2 (m, 2H), 3.6-3.8 (br s , 2H), 4.3 (q, 2H), 4.7 (s, 2H), 7.0-7.1 (m, 3H), 7.15 (s, 1H), 7.3 (m, 2H), 7.4 (s, 1H).

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Method 9

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

The 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 8; 0.34 g) and sodium hydroxide (0.3 g) were dissolved in ethanol, and the mixture was heated at reflux for 1 hour. Was added acetic acid (1 ml), and the solvent was removed under reduced pressure. The residue was partitioned between DCM / H2O, and the organic layer was separated and dried. Crushing the residue with n-hexane gave 0.29 g of the title compound (90%) Like a solid NMR (500 MHz) 0.7-0.8 (m, 6H), 1.0-1.7 (m, 8H), 3.1-3.2 (m, 2H), 3.6 (br s, 2H), 4.6 (s, 2H), 6.9-7.1 (m, 4H), 7.2 (m, 2H), 7.5 (s, 1H).

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Method 10

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

It dissolved 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 7; 1.2 g) in ethanol (20 ml). Sodium hydroxide was added (0.5 g) dissolved in water (1 ml), and the reaction mixture was heated up to 40 ° C for 30 minutes. Acetic acid (1 ml) was added, and the Solvent was removed under reduced pressure. The residue was divided between DCM / H2O, and the organic layer was separated and dried. The trituration of the residue with n-hexane gave 1.1 g of title compound (97%) as a solid. NMR 0.75-0.85 (m, 3H), 0.9 (t, 3H), 1.0-1.7 (m, 8H), 3.2 (q, 2H), 3.65 (s, 3H), 3.65-3.85 (m, 2H), 4.7 (s, 2H), 6.4 (s, 1H), 7.0 (t, 1H), 7.1 (d, 2H), 7.3 (t, 2H), 7.5 (s, 1H).

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Method eleven

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

They were added 1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (synthesized as described in WO9616051 for the analogue of 3-butyl-3-ethyl correspondent; 2.0 g, 4.16 mmol), ethyl bromoacetate (0.84 g, 5.03 mmol), sodium carbonate (2.0 g, 18.9 mmol) and bromide from tetrabutylammonium (80 mg, 0.25 mmol) to MeCN (20 ml). Mix it was heated at reflux for 2 hours, and then evaporated under pressure reduced The residue was extracted with DCM / water. The DCM layer is separated and evaporated under reduced pressure. The residue was purified by column chromatography. The product was eluted with DCM / EtOAc (90:10) to give 2.2 g of the title compound (93%). NMR 0.7-0.8 (m, 6H), 1.0-1.6 (m, 15H), 3.2 (br s, 2H), 3.7 (br s, 2H), 4.3 (q, 2H), 4.7 (s, 2H), 7.0-7.3 (m, 6H), 7.4 (s, 1H).

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Methods 12-13

The following compounds were synthesized by the method of Method 11, using the acid and the amine appropriate (source not indicated where it is commercially available).

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Method 14

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine was dissolved
(Method 11; 2.2 g, 3.88 mmol) in ethanol (15 ml). NaOH (0.8 g in 1.5 ml water) was added to the solution, and the mixture was stirred for 30 minutes at room temperature. Acetic acid (2 ml) was added. The solvent was evaporated under reduced pressure, and the residue was extracted with EtOAc / water. The EtOAc layer was separated, dried and evaporated under reduced pressure to give the title compound 2.0 g (95%). NMR (500 MHz) 0.7-0.8 (m, 6H), 1.0-1.5 (m, 12H), 3.2 (br s, 2H), 3.7 (br s, 2H) , 4.7 (s, 2H), 7.0-7.3 (m, 6H), 7.4 (s, 1H).

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Method fifteen

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-isopropoxy-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To isopropyl alcohol (12 ml) sodium was added (115 mg, 5 mmol), and the temperature was then raised to 80 ° C to let the salt of alcohol form. After all the sodium dissolved, was added 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 9; 100 mg, 0.2 mmol) in a single serving. The reaction is then heated to reflux overnight, and then cooled to room temperature and was paralyzed with acetic acid. Solvent it was then removed under reduced pressure, and the residue was dissolved in water and MeCN (70/30), and was partially purified by HPLC. He residue was dissolved in ethylene glycol, and NaOH (500 mg) was added. This reaction mixture was heated at 125 ° C overnight, and then cooled to room temperature and paralyzed with acid acetic, and EtOAc (100 ml) was added. The ethylene glycol was removed washing the organic layer three times with acidic water. The layer organic was then concentrated, and the residue was purified again as described above, to give 40 mg of the compound of title (41%). NMR (300 MHz) 0.7-1.0 (m, 6H), 1.0-1.8 (m, 15H), 3.2 (q, 2H), 3.75 (m, 2H), 4.3 (m, 1H), 4.6 (s, 2H), 6.35 (s, 1H), 6.95-7.2 (m, 3H), 7.2-7.4 (m, 2H), 7.55 (s, 1H).

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Method 16

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 25; 500 mg, 1.2 mmol) MeCN (30 ml), bromide tetrabutylammonium (30 mg, 0.08 mmol), anhydrous sodium carbonate (500 mg, 4.7 mmol), ethyl bromoacetate (0.14 ml, 1.26 mmol) and cesium carbonate (20 mg, 0.06 mmol). This reaction mixture is then stirred overnight at 80 ° C. Then, the solvent was removed at reduced pressure, water and DCM were added, and the aqueous phase was extracted three times with DCM. The combined organic phases are then dried, concentrated and purified by flash chromatography [DCM: EtOAc, 1: 0, 9: 1] to give 600 mg of the title compound (99%). NMR (300 MHz) 0.8-1.0 (m, 6H), 1.0-1.8 (m, 11H), 2.2 (s, 3H), 3.2 (q, 2H) 3.75 (br q, 2H), 4.3 (q, 2H), 4.75 (s, 1H), 6.7 (s, 1H), 6.95 (t, 1H), 7.05 (d, 2H), 7.25 (t, 2H), 7.3 (s, 1 HOUR).

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Method 17

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 16; 478 mg, 0.95 mmol) THF (15 ml), water (3 ml) and LiOH (34 mg, 1.4 mmol). The reaction was then stirred for 1 hour. Then, acetic acid (0.2 ml) was added along with water (10 ml) and DCM (10 ml). The aqueous layer was then extracted three times with DCM The combined organic phases were then dried and concentrated to give 450 mg of the title compound (99%). NMR 0.7-0.9 (m, 6H), 1.0-1.7 (m, 8H), 2.2 (s, 3H), 3.2 (q, 2H), 3.7 (m, 2H), 4.8 (s, 2H), 6.65 (s, 1H), 6.95 (t, 1H), 7.05 (d, 2H), 7.25 (t, 2H), 7.35 (s, 1H), 8.4 (br s, 1 HOUR).

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Method 18-19

The following compounds were synthesized by the method of Method 17, using the acid and the amine appropriate (source not indicated when commercially available), except that two equivalents of LiOH were used, and the Extraction was performed after a reaction time of 2 hours using EtOAc.

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Method twenty

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-mesyl-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

TO 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 16; 122 mg, 0.24 mmol) DCM (3 ml), water (3 ml) was added and potassium carbonate (120 mg, 0.87 mmol). Reaction mixture it was then cooled to 0 ° C, and acid was added m-chloroperoxybenzoic acid (160 mg, 0.51 mmol) in one single serving After 5 hours, the reaction was stopped with DCM and saturated sodium hydrogen carbonate solution, the aqueous phase It was then extracted three times with DCM. The combined organic phases dried, concentrated and purified by chromatography ultrafast [DCM: EtOAc, 9: 1] to give 46 mg of the compound of title (35%). NMR 0.7-0.8 (m, 6H), 1.0-1.65 (m, 11H), 3.2 (q, 2H), 3.3 (s, 3H), 3.7 (br s, 1H), 4.25 (q, 2H), 4.8 (s, 2H), 7.0-7.1 (m, 3H), 7.2-7.3 (m, 2H), 7.5 (s, 2H).

Method twenty-one

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-mesyl-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-mesyl-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 20; 46 mg, 0.085 mmol) THF (5 ml), water (1 ml) was added and LiOH (10 mg, 0.4 mmol). The reaction was stirred for 1 hour, and then an excess of acetic acid was added to paralyze the reaction. Water and DCM were added, and the aqueous layer was extracted three times with DCM. The combined organic phases were dried and concentrated to give 40 mg of the title compound (91%). 0.7-0.85 (m, 6H), 1.0-1.7 (m, 8H), 3.2 (m, 2H), 3.3 (s, 3H), 3.8 (s, 2H), 4.9 (s, 2H), 5.0 (br s, 1H), 7.05-7.15 (m, 3H), 7.3-7.4 (t, 2H), 7.5 (s, 1 H), 7.6 (s, 1 H).

Method 22 (Preparation one)

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

The 1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetranidro-1,5-benzothiazepine (Method 14; 500 mg, 0.93 mmol) was dissolved in DMF (10 ml). Be Sodium methanethiolate (200 mg, 2.85 mmol) was added, and the mixture was stirred for 2 hours at 50 ° C. Acetic acid (0.4 ml) was added, and the solvent was evaporated under reduced pressure. The residue was extracted with EtOAc / water. The EtOAc layer was separated, dried and evaporated to reduced pressure to give 450 mg of the title compound (96%). NMR (300 MHz) 0.7-0.8 (m, 6H), 1.0-1.6 (m, 12H), 2.2 (s, 2H), 3.2 (br s, 2H), 3.7 (br s, 2H), 4.8 (s, 2H), 6.6 (s, 1H), 6.9-7.1 (m, 3H), 7.2-7.4 (m, 3H).

Method 22 (Preparation 2)

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

A solution of NaOH (4.67 g, 116 mmol) in water (10 ml) was added to a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonyl-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 114; 15.45 g, 28.71 mmol) in EtOH (160 ml). Dissolution It was stirred for 30 minutes at room temperature. Solvent it was removed under reduced pressure, and the residue was partitioned between EtOAc and 1.0 M HCl. The aqueous layer was extracted twice more with EtOAc, and The combined organic extracts were washed with brine and concentrated to give the title compound (14.28 g, 98%) as a white powder NMR (500 MHz, DMSO-d6) 0.65-0.80 (m, 6H), 0.90-1.50 (m, 12H), 2.20 (s, 3H), 3.25 (s, 2H), 3.65 (bs, 2H), 4.80 (s, 2H), 6.70 (s, 1H), 6.80-7.30 (m, 6H), 13.20 (s, 1H).

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Method 23-24

The following compounds were synthesized by the method of Method 22 (Preparation 1), using the appropriate acid and amine (source not indicated when commercially available), except that the reactions are performed at room temperature and, in Method 24, during a prolonged reaction time.

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Method 25

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (docuemnto
WO9616051; 600 mg, 1.29 mmol) DMF (5 ml) and sodium methanethiolate (450 mg, 6.42 mmol) were added. The reaction was then heated at 60 ° C for 1 hour. The oil bath was then heated to 120 ° C for 4 hours. To paralyze the reaction, the temperature was lowered to room temperature, and excess acetic acid was quickly added. The reaction was maintained in a flow of nitrogen through sodium hypochlorite, for 2 hours. Water and EtOAc were added, and the aqueous layer was extracted three times with EtOAc. The combined organic phases were washed with water, dried and concentrated under reduced pressure. The residue was then purified by flash chromatography [DCM: EtOAc, 9: 1] to give 0.5 g of the title compound (92%). NMR 0.65-0.8 (m, 6H), 0.95-1.6 (m, 8H), 3.1 (q, 2H), 3.6 (brq, 2H), 6.75 (s , 1H), 6.8 (t, 1H), 6.9 (d, 2H), 7.15 (t, 2H), 7.55 (s, 1H).

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Method 26

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To 1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (synthesized as described in WO9616051 for the corresponding analog 3-butyl-3-ethyl; 40 mg, 0.08 mmol) DMF (2 ml), sodium methanethiolate (60 mg, 0.85 mmol) and sodium borohydride (60 mg, 1.6 mmol). The reaction was carried out overnight at 60 ° C. Borohydride was added of additional sodium (60 mg, 1.6 mmol) and sodium methanethiolate (60 mg, 0.85 mmol), and the temperature rose to 120 ° C. The reaction it was heated at this temperature for 4 hours, and then cooled up to room temperature Then, acetic acid was added in a nitrogen flow, through sodium hypochlorite, overnight. Water and EtOAc were added, and the aqueous layer was extracted three times with EtOAc The combined organic phases were washed with HCl (1M), dried and concentrated under reduced pressure. The residue was purified then by flash chromatography [EtOAc: heptane, 1: 4] to give 0.34 g of the title compound (93%). NMR 0.7-0.9 (m, 6H), 1.0-1.6 (m, 12H), 2.2 (s, 3H), 3.1 (s, 2H), 3.4 (s, 2H), 3.7 (br s, 2H), 6.7 (s, 1H), 6.85-7.05 (m, 2H), 7.2-7.4 (m, 2H).

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Method 27

2 - [(2'R) -2 '- ( t -butoxycarbonylamino) -2'-phenylethanylamino] ethanesulfonic acid ammonium salt

2-Aminoethanesulfonic acid (740 mg, 5.91 mmol) and (2R) -2- ( t -butoxycarbonylamino) -2-phenylacetic acid (1.09 g, 4.34 mmol) were dissolved in DMF (20 ml ). DIPEA (2.8 ml, 16.1 mmol) and TBTU (1.53 g, 4.78 mmol) were added, and the mixture was stirred for 2 hours at 60 ° C. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC, using a gradient of MeCN / ammonium acetate buffer (5/95 to 100/0) as eluent, to give 589 mg of the title compound (32%). NMR (CD 3 OD) 1.43 (s, 9H), 2.85-3.0 (m, 2H), 3.53-3.68 (m, 2H), 5.1 (br s, 1H), 7.25-7.45 (m, 5H).

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Method 28

Acid ammonium salt 2 - ((2'R) -2'-amino-2'-phenylethanylamino) ethanesulfonic acid

The ammonium salt of 2 - [(2'R) -2 '- ( t -butoxycarbonylamino) -2'-phenyletanoylamino] ethanesulfonic acid (Method 27; 589 mg, 1.57 mmol) was dissolved in EtOAc (20 ml) , and the mixture was cooled in an ice bath. Hydrogen chloride gas was bubbled through the reaction, the ice bath was removed, and the reaction was allowed to stand for 30 minutes at room temperature. The solvent was evaporated under reduced pressure. The residue was then redissolved in EtOAc (20 ml), and cooled in an ice bath. Hydrogen chloride gas was bubbled again through the reaction, the ice bath was removed, and the reaction was allowed to stand for 30 minutes at room temperature. The solvent was evaporated under reduced pressure. DIPEA in DCM was added, and the mixture was evaporated under reduced pressure. This was repeated twice. The mixture was lyophilized to give the title compound 563 mg (85%) containing 1 equivalent of di-isopropylethylammonium chloride. NMR (D 2 O) 1.35-1.38 (m, 15H), 2.96-3.12 (m, 2H), 3.21 (q, 2H), 3.50-3.80 (m, 4H), 5.11 (br s, 1H), 7.45-7.55 (m, 5H).

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Method 29

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - ((R) -1'-phenyl-1'-methoxycarbonylmethyl) carbamoylmethoxy] -2,3,4,5 -tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine was dissolved
(Method 22; 250 mg, 0.49 mmol), (R) -2-phenylglycine methyl ester hydrochloride (120 mg, 0.60 mmol) and DIPEA (300 mg, 2.3 mmol) in DCM ( 10 ml), and the mixture was stirred for 5 minutes at room temperature. TBTU (210 mg, 0.65 mmol) was added, and the mixture was stirred for 30 minutes at room temperature. The solvent was evaporated under reduced pressure, and the residue was placed on a column and the product was eluted with DCM / EtOAc (90:10) to give 306 mg of the title compound (95%). NMR (500 MHz) 0.7-0.8 (m, 6H), 1.0-1.6 (m, 12H), 2.1 (s, 3H) 3.2 brs, 2H), 3.6 -3.8 (m, 5H), 4.6 (ABq, 2H), 5.6 (d, 1H), 6.6 (s, 1H), 6.9-7.5 (m, 11H), 7.9 (d, 1 H).

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Methods 30-45

The following compounds were synthesized by the method of Method 29, using the acid and the amine appropriate (source not indicated when commercially available), except that the reaction time was extended up to 2 Hours for some methods.

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70

71

72

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Method 46

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- [ N - ((S) -1'-phenyl-1'-methoxycarbonylmethyl) carbamoylmethoxyl-2,3,4, 5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 9; 50 mg, 0.098 mmol) was dissolved in DCM (2 ml). (2 S ) -amino (phenyl) methyl acetate (19 mg, 0.12 mmol) and DIPEA (0.068 ml, 0.39 mmol) were added, and the reaction was stirred for 2 minutes. TBTU (42 mg, 0.13 mmol) was added, and the mixture was stirred for 1.5 hours at room temperature. The mixture was placed on a prepackaged ISOLUTE column, and eluted with 10 ml of 8/2 DCM / EtOAc to give 60 mg of the title compound (93%). M / z 657.5.

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Methods 47-62

The following compounds were synthesized by the method of Method 46 (except that the times of reaction lasted all night), using acid and amine appropriate (source not indicated when commercially available).

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Method 63

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N {(R) -1'-phenyl-1 '- [N' - ( t -butoxycarbonylmethyl) carbamoyl] methyl} -carbamoyl-methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - ((R) -1'-phenyl-l'-carboxymethyl) carbamoylmethoxy] -2,3,4, 5-tetrahi-
dro-1,5-benzothiazepine (Example 1; 110 mg, 0.17 mmol), glycine tert-butyl ester (30 mg, 0.23 mmol) and DIPEA (120 mg, 0.93 mmol) were dissolved in DCM (2 ml). The mixture was stirred for 5 minutes at room temperature. TBTU (72 mg, 0.22 mmol) was added, and the mixture was stirred for 1 hour at room temperature. The solvent was evaporated under reduced pressure, and the residue was placed on a column and the product was eluted with DCM / EtOAc (90:10) to give 122 mg of the title compound (94%). NMR (300 MHz) 0.7-0.8 (m, 6H), 1.0-1.6 (m, 21H), 2.2 (s, 3H) 3.2 (s, 2H), 3, 7-4.0 (m, 4H), 4.6 (ABq, 2H), 5.6 (d, 1H), 6.4 (t, 1H), 6.6 (s, 1H), 6.9 -7.5 (m, 11H), 8.1 (d, 1H).

Methods 64-69

The following compounds were synthesized by the method of Method 63, using the acid and the amine appropriate (source not indicated when commercially available).

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Method 70

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- { N - [(S) -1'-phenyl-1 '- (diethoxyphosphoryl) methyl] carbamoylmethoxy} -2, 3,4,5-tetra-hydro-1,5-benzothiazepine

The title compound was synthesized from the 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 9) and (S) amino (phenyl) methylphosphonate of diethyl by the procedure of Example 33. NMR (600 MHz) 7.77-7.72 (1H, m), 7.47-7.42 (3H, m), 7.36-7.27 (5H, m), 7.14 (1H, s), 7.10-7.03 (2H, m), 5.55-5.48 (1H, m), 4.63-4.51 (2H, m), 4.14-4.02 (2H, m), 3.99-3.92 (1H, m), 3.81-3.60 (3H, m), 3.22-3.10 (2H, m), 1.65-1.25 (8H, m), 1.19-0.95 (6H, m), 0.78-0.73 (6H, m).

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Method 71

4-Trifluoromethyl-? -Methoxycarbonylbenzylamine

The 4-trifluoromethyl-? -Carboxybenzylamine (1.4 g, 1.83 mmol) and thionyl chloride were added to methanol (8 ml), and the mixture was heated at reflux for 2 hours. He solvent was evaporated under reduced pressure. The residue was suspended in diethyl ether, and the product was filtered, washed with ether and dried to give the title compound 0.34 g (69%). NMR (300 MHz, DMSO-d6) 3.3 (s, 1H), 5.45 (s, 1H), 7.7-7.9 (m, 4H), 9.25 (br s, 3H).

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Method 72

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [ N - (ethoxycarbonylmethyl) carbamoyl] methyl} -carbamoyl-methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2,3, 4,5-tetrahydro-1,5-benzothiazepine (Example 38; 52 mg, 0.082 mmol) and glycine ethyl ester hydrochloride (18 mg, 0.129 mmol) were dissolved in DCM (2 ml), and DIPEA was added (0.70 ml, 0.42 mmol). After stirring at room temperature for 5 minutes, TBTU (34 mg, 0.11 mmol) was added, and the mixture was stirred for 2 hours. The solvent was evaporated, and the residue was purified with flash chromatography (DCM: 10: 3 EtOAc) to give 50 mg of the title compound (88%). NMR (500 MHz) 0.86 (m, 6H), 1.10-1.75 (m, 8H), 1.28 (m, 3H), 2.23 (s, 3H), 3.19 (q , 2H), 3.75 (m, 2H), 3.99-4.25 (m, 4H), 4.64 (q, 2H), 5.64 (m, 1H), 6.35 (br s , 1H), 6.69 (s, 1H), 7.03 (t, 1H), 7.09 (d, 1H), 7.29-7.52 (m, 7H), 8.10 (d, 1 HOUR).

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Method 73

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [ N - (1''- methoxycarbonyl- 1 '' - phenylmethyl) carbamoyl] -methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

The title compound was synthesized by Method 72 procedure using the 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [N - ((R) -1'-phenyl-1'-carboxymethyl) carbamoylmethoxy] -2,3,4 , 5-tetrahydro-1,5-benzothiazepine (Example 38) and the hydrochloride of (2R) amino (phenyl) methyl acetate.

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Method 74

Hydrochloride salt 1- (1'-methoxycarbonyl-1'-aminomethyl) -2,3-dihydroxyphenyl

He 1- (1'-carboxy-1'-aminomethyl) -2,3-dihydroxyphenyl (40 g, 0.218 mmol) was mixed with methanol (230 ml). Made Bubble gaseous HCl through it. The mixture was heated to reflux. for 2 hours The solvent was evaporated under reduced pressure. He product was crystallized from methanol / EtOAc / diethyl ether, to produce 35.5 g (70%) of the title compound. NMR (600 MHz, CD 3 OD) 3.76 (s, 3H), 5.19 (s, 1H), 6.68-6.75 (m, 2H), 6.85 (dd, 1H).

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Method 75

Hydrochloride salt (R) -1- (1'-methoxycarbonyl-1'-aminomethyl) -4-fluorophenyl

Acid (2R) -amino (4-fluorophenyl) acetic (570 mg, 2.77 mmol) was dissolved in methanol (5 ml), and cooled in an ice bath Thionyl chloride (2 ml) was added dropwise, and the temperature was allowed to reach room temperature. After 5 hours, the mixture was evaporated under reduced pressure. He procedure was repeated, and the reaction was stirred overnight. The mixture was evaporated under reduced pressure to give the compound of Title with quantitative performance. NMR (500 MHz, CD 3 OD) 3.84 (s, 3H), 5.26 (s, 1H), 7.26 (t, 2H), 7.53 (dd, 2H).

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Methods 76-77

The following compounds were synthesized by the method of Method 75, using the acid and the amine appropriate (source not indicated when commercially available).

81

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Method 78

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- { N - [(R) - α- ( t -butoxycarbonyl) -4-hydroxybenzyl] carbamoylmethoxy} -2, 3,4,5-tetrahydro-1,5-benzothiazepine

(2R) -amino (4-hydroxyphenyl) tert -butyl acetate (104 mg, 0.47 mmol) and 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8 -carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 17; 185 mg, 0.39 mmol) was dissolved in DCM (5 ml), and lutidine (0.09 ml, 0 was added , 77 mmol). After stirring at room temperature for 5 minutes, O- (7-azabenzotriazol-1-yl) - N, N, N ', N' -tetramethyluronium hexafluorophosphate (208 mg, 0.55 mmol) was added, and the mixture The reaction was stirred at room temperature for 2 hours. Purification with flash chromatography (DCM: EtOAc 10: 1 -> 5: 1) gave the title compound (175 mg, 66%). NMR (300 MHz) 0.81 (m, 6H), 1.05-1.65 (m, 8H), 1.42 (s, 9H), 2.21 (s, 3H), 3.17 (ABq , 2H), 3.74 (m, 2H), 4.60 (ABq, 2H), 5.22 (br s, 1H), 5.49 (d, 1H), 6.67 (s, 1H), 6.79 (m, 2H), 7.00 (t, 1H), 7.07 (d, 2H), 7.23-7.30 (m, 3H), 7.40 (s, 1H), 7 , 82 (br d, 1 H).

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Method 79

The following compounds were synthesized by the method of Method 78, using the material of appropriate game

83

Method 80

Acid 2 - {[(2R) -2-amino-2- (4-hydroxyphenyl) ethanoyl] amino} -ethanesulfonic acid

The N-Boc-4-hydroxyphenylglycine (1.00 g, 3.21 mmol) was dissolved in DMF (5 ml), and taurine was added of tetrabutylammonium (2.36 g, 6.42 mmol) together with 5 ml additional DMF. The resulting suspension was cooled on ice, and TBTU (1.24 g, 3.85 mmol) was added. The ice bath was removed after 30 minutes, and the mixture was stirred for 2 hours before that it will be filtered and concentrated. TFA in DCM (20%, 20 ml), and the reaction mixture was stirred overnight. Was added ethanol (20 ml), and the solvents evaporated. The gross product is heated to reflux in ethanol (100 ml) for 1 hour. Filtration produced the pure title compound as a white solid, 626 mg (71%). NMR (DMSO-d6) 2.4-2.6 (m, 2H), 3.2-3.4 (m, 2H), 4.79 (s, 1H), 6.78 (d, 2H), 7.23 (d, 2H), 8.22 (t, 1H), 8.4 (br s, 3H), 9.7 (s, 1H).

Method 81

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-carboxymethylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

The 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (113 mg, 0.24 mmol), cesium carbonate (170 mg, 0.52 mmol) and ethyl thioglycolate (0.060 ml, 0.54 mmol) in DMF (4.0 ml) is subjected to microwave irradiation in a Smith Synthesizer to 80 ° C for 3 minutes, and then at 90 ° C for 8 minutes. Mix The reaction was diluted with water (250 ml), and extracted with DCM (5 x 10 ml), and the collected organic layers were dried (MgSO4), dried concentrated and purified on a short column (ether of petroleum: EtOAc 4: 1 -> 2: 1). The resulting product was dissolved in THF (2 ml) and water (2 ml), and NaOH (aqueous, 0.5 ml, 1 M) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction was paralyzed with HCl (1 M), and the mixture of reaction was diluted with water (10 ml), and extracted with DCM (3 x 3 ml) Purification with preparative HPLC produced the compound of titer (58 mg, 59%). NMR (300 MHz, CD 3 OD) 0.81 (m, 6H), 1.00-1.70 (m, 8H), 3.21 (m, 2H), 3.42 (m, 2H), 3.71 (m, 2H), 3.92 (s, 3H), 6.88 (m, 2H), 7.02 (m, 2H), 7.23 (t, 2H), 7.40 (s, 1 H).

Method 82

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-ethoxycarbonylmethylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

The 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 9; 50 mg, 0.098 mmol) and cesium carbonate (51 mg, 0.15 mmol) was added to DMF (2 ml), and thioglycolate was added ethyl (0.02 ml, 0.15 mmol). The reaction mixture was subjected to microwave irradiation in a Smith Synthesizer at 150 ° C for 5 minutes. The reaction mixture was diluted with water (100 ml), acidified with HCl (1 M), extracted with DCM (3 x 10 ml), and Collected organic layers were dried (MgSO4) to give the crude title compound (54 mg). M / z 550.2.

Method 83 and Method 84

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Enantiomer 1)

Y

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Enantiomer 2)

The two enantiomers of the 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (WO 96/16051) were obtained by separating the corresponding racemic mixture using preparative HPLC. The column used was a Chiralpak AD (20x250 mm in diameter internal, 10 µm), and the mobile phase was a mixture of heptane / IPA in a ratio of 90/10. Injected racemate (17.3 mg in IPA (1 ml)) was eluted at a flow rate of 10 ml / min, and the chromatogram was followed with UV detection at 285 nm. In total 260 mg were separated of racemate, producing 121 mg of the first eluting enantiomer (Enantiomer 1) and 115 mg of the second eluting enantiomer (Enantiomer 2). Total yield 91%. Each of the two enantiomers was obtained in 99.4% e.e.

Method 85

(R) - N- Benzyloxycarbonyl-? - [ N '- ( t -butoxycarbonylmethyl) -carbamoyl] benzylamine

The (R) - N -benzyloxycarbonyl-? -Carboxybenzylamine (10 g, 35.0 mmol) and t-butylglycine hydrochloride (6.3 g, 37.4 mmol) were dissolved in DCM (200 ml) with 2 , 6-lutidine (8.2 ml, 70.4 mmol). After stirring 5 minutes at 0 ° C, TBTU (12.4 g, 38.6 mmol) was added, and stirring was continued 1 hour 30 minutes at 0 ° C, and 3 hours 45 minutes at room temperature. The reaction mixture was washed with water (2 x 100 ml), dried (MgSO 4) and purified with flash chromatography (DCM: EtOAc 7: 1 -> 5: 1) to give the title compound (13 g, 94%). NMR (500 MHz) 1.45 (s, 9H), 3.84 (d, 1H), 4.00 (dd, 1H), 5.10 (m, 2H), 5.28 (br s, 1H) , 6.13 (br s, 1H), 6.23 (br s, 1H), 7.30-7.44 (m, 10H).

Method 86

(R) -? - [ N - ( t -Butoxycarbonimethyl) carbamoyl] benzylamine

The (R) - N -benzyloxycarbonyl-? - [ N '- ( t -butoxycarbonyl-methyl) carbamoyl] benzylamine (Method 85; 12.8 g, 32.2 mmol) was dissolved in EtOH (99%, 200 ml ) and toluene (50 ml). Pd / C (10%, 0.65 g) was added, and hydrogenation was performed at atmospheric pressure for 5 hours 30 minutes at room temperature. The reaction mixture was filtered through diatomaceous earth, and the solvents were evaporated to give the title compound (8.4 g, 99%). NMR (600 MHz) 1.45 (s, 9H), 3.93 (m, 2H), 4.54 (s, 1H), 7.31-7.42 (m, 5H), 7.51 (br s, 1H).

Method 87

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - (S) - (α-methoxycarbonylbenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1, 5-benzothiazepine

The 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 22; 50 mg, 0.099 mmol) was dissolved in DCM (2 ml). Be added methyl ester hydrochloride of the (S) -phenylglycine (24.8 mg, 0.123 mmol) and diisopropylethylamine (70 µL, 0.401 mmol). The mixture was stirred. for 15 minutes, and then TBTU (38 mg, 0.118 mmol) was added. The reaction was finished after 1.5 hours (LC / MS). He crude product was purified by flash chromatography using chloroform / EtOAc (8/2) as the eluent (88.6%; 55.2 mg, 0.064 mmol). M / z 653.

Method 88

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - (S) -? - [ N '- (methoxycarbonylmethyl) carbamoyl] benzyl} carbamoylmethoxy] -2,3, 4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [ N - (S) - (α-carboxybenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1 ,5-
Benzothiazepine (Example 88; 25 mg, 0.039 mmol) and glycine methyl ester (7.5 mg, 0.059 mmol) were dissolved in DCM (2 ml). Diisopropylethylamine (27 µL, 0.158 mmol) and TBTU (15 mg, 0.047 mmol) were added successively, and the mixture was stirred for 2 hours at room temperature. The crude product was purified by flash chromatography using DCM / EtOAc (8/2) as eluent, 79% yield (22 mg). M / z 710.

Method 89

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- (2-carboxyethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine

Sodium hydroxide was dissolved (38 mg, 0.95 mmol) in ethanol (2.5 ml), and then added 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (WO 96/16051; 200 mg, 0.443 mmol). After stirring to room temperature for 5 minutes, acid was added 3-bromopropionic (68 mg, 0.443 mmol), and the mixture The reaction was heated at reflux for 20 hours. Acid was added acetic. The solvent was evaporated under reduced pressure, and the residue It was extracted with EtOAc / water. The organic layer was separated, washed with water, dried and evaporated under reduced pressure. The gross product is purified by column chromatography using DCM / MeOH (100: 5) as eluent, to give the title compound 89 mg (38%). NMR (CD 3 OD) 0.75-0.83 (m, 6H), 1.0-1.25 (m, 4H), 1.38-1.65 (m, 4H),  2.82 (m, 2H), 3.26 (s, 2H), 3.50-3.90 (m, 2H), 4.33 (t, 2H), 6.99 (t, 1H), 7.07-7.13 (m, 3H), 7.28 (t, 2H), 7.53 (s, 1H).

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Method 90

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- (2- { N - [(R) - α- ( t -butoxycarbonyl) benzyl] carbamoyl} ethoxy) - 2,3,4,5-tetrahi-dro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8- (2-carboxyethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine ( Method 89; 70 mg, 0.134 mmol) and (R) -? - ( t -butoxycarbonyl) benzylamine (J. Amer. Chem. Soc .; EN; 117; 44; 1995; 10879-10888; 35 mg, 0.169 mmol ) in DCM (2.5 ml) 2,6-lutidine (29 mg, 0.268 mmol) and TBTU (56 mg, 0.174 mmol) were added. The reaction mixture was stirred at room temperature for 2.5 hours, then diluted with DCM. The solution was washed with NaHCO3 (aqueous, saturated), with water, dried, and the solvent was evaporated under reduced pressure. The residue was suspended in ether / petroleum ether, and the crystals were filtered to give the title compound 85 mg (89%). NMR (500 MHz) 0.79-0.86 (m, 6H), 1.04-1.28 (m, 4H), 1.35-1.56 (m, 11H), 1.60-1, 77 (m, 2H), 2.82 (t, 2H), 3.13-3.25 (m, 2H), 3.72 (br s, 2H), 4.35-4.44 (m, 2H ), 5.54 (d, 1H), 6.95 (d, 1H), 7.04 (t, 1H), 7.08 (d, 2H), 7.15 (s, 1H), 7.29 -7.43 (m, 6H), 7.52 (s, 1H).

Methods 91-94

The following compounds were synthesized by the procedure of Example 104, using the material of appropriate heading (source of amine indicated when not commercially available).

84

85

86

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Method 95

3,3-Dibutyl-4-oxo-5- (4-chlorophenyl) -7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

A mixture of 3,3-dibutyl-4-oxo-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 95 /
04534; 1.0 g, 2.5 mmol), 4-bromochlorobenzene (4.78 g, 24.98 mmol), copper bromide (36 mg, 0.25 mmol) and potassium carbonate (0.35 g, 2, 5 mmol) was heated at reflux for 20 hours. The reaction mixture was loaded on a column, and the product eluted with 5% EtOAc / petroleum ether (0.8 g, 63% yield). NMR (500 MHz) 0.86-0.92 (m, 6H), 1.16-1.35 (m, 8H), 1.45-1.65 (m, 4H), 3.16 (s, 2H), 3.96 (s, 3H), 7.06-7.10 (m, 2H), 7.19 (s, 1H), 7.29 (s, 1H), 7.33-7.38 (m, 2H). M / z 511.

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Method 96

1,1-Dioxo-3,3-dibutyl-4-oxo-5- (4-chlorophenyl) -7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a mixture of 3,3-dibutyl-4-oxo-5- (4-chlorophenyl) -7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 95; 0.67 g, 1.304 mmol), DCM (34 ml), water (34 ml) and potassium carbonate (0.554 g, 4.0 mmol) was added, at 0 ° C, acid m-chloroperoxybenzoic acid (0.78 g, 3.2 mmol) in one single serving The reaction mixture was stirred at 0 ° C for 10 hours, and then at room temperature for 14 hours. Was added DCM (100 ml), and NaHCO 3 (aqueous, saturated; 150 ml). The layer Organic was separated, washed with brine, dried and evaporated to reduced pressure to give 0.68 g of the title compound (96%). NMR (600 MHz) 0.7-0.92 (m, 6H), 1.0-1.60  (m, 10H), 1.70-1.92 (m, 2H), 2.30-3.7 (m, 2H), 3.99 (s, 3H), 7.16-7.20 (m, 2H), 7.24 (s, 1H), 7.34-7.37 (m, 2H), 7.44 (s, 1H); m / z 543.

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Method 97

1,1-Dioxo-3,3-dibutyl-4-oxo-5- (4-chlorophenyl) -7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

Sodium methanethiolate (0.43 g, 6.08 was added mmoles) to a solution of 1,1-dioxo-3,3-dibutyl-4-oxo-5- (4-chlorophenyl) -7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 96; 0.66 g, 1.22 mmol) in anhydrous DMF (11 ml), in nitrogen atmosphere The reaction mixture was stirred at room temperature for 72 hours. The solvent was evaporated at reduced pressure, and the residue was extracted with trichloromethane / water. The organic layer was separated, washed with brine, dried and dried. evaporated under reduced pressure. The crude product was purified by column chromatography, using DCM as the eluent, to give 0.6 g of the title compound (96%). NMR (500 MHz) 0.80-1.0 (m, 6H), 1.10-1.6 (m, 10H), 1.70-2.0 (m, 2H), 2.28 (s, 3H), 3.37-3.70 (m, 2H), 4.04 (s, 3H), 6.65 (s, 1H), 7.25-7.30 (m, 2H), 7.35-7.42 (m, 3H); m / z 510.4.

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Method 98

1,1-Dioxo-3,3-dibutyl-5- (4-chlorophenyl) -7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

At a dissolution of 1,1-dioxo-3,3-dibutyl-4-oxo-5- (4-chlorophenyl) -7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 97; 0.41 g, 0.79 mmol) in anhydrous ether (15 ml) was added LiAlH 4 (0.15 g, 3.97 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction flask was cooled to 0 ° C, and the LiAlH4 in excess it was paralyzed by the addition of water (0.3 ml) and 2 M aqueous NaOH  (0.3 ml). The mixture was filtered, and the filtrate was dried and evaporated to reduced pressure The crude product was purified by column chromatography, using DCM as the eluent, to give 0.265 g of the title compound (68%). NMR (300 MHz) 0.8-0.90 (m, 6H), 1.0-1.47 (m, 12H), 2.33 (s, 3H), 3.17 (s, 2H), 3.70 (s, 2H), 3.93 (s, 3H), 7.03-7.08 (m, 3H), 7.23-7.32 (m, 3H); m / z 496.

Method 99

1,1-Dioxo-3,3-dibutyl-5- (4-chlorophenyl) -7-methylthio-8-hydroxy-2-3,4,5-tetrahydro-1,5-benzothiazepine

At a dissolution of 1,1-dioxo-3,3-dibutyl-5- (4-chlorophenyl) -7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 98; 0.26 g 0.52 mmol) in anhydrous DCM (10 ml) was added boron tribromide (2.63 g, 10.48 mmol) in an atmosphere of nitrogen. The reaction mixture was stirred at room temperature. for 2.5 hours The reaction flask was cooled to 0 ° C, it was they added water (20 ml) and hydrazine monohydrate (0.5 ml). The layer Organic was separated, dried and evaporated under reduced pressure. He crude product was purified by column chromatography, using DCM / EtOAc (100: 5 and 100: 10) as the eluent, to give 0.20 g of the title compound (80%). NMR (500 MHz) 0.85 (t, 6H), 1.03-1.28 (m, 8H), 1.35-1.46 (m, 4H), 2.39 (s, 3H), 3.21 (s, 2H), 3.73 (s, 2H), 7.04 (d, 2H), 7.29-7.34 (m, 3H), 7.44 (s, 1H); m / z 482.

Method 100

1,1-Dioxo-3,3-dibutyl-5- (4-chlorophenyl) -7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

Ethyl bromoacetate (0.101 g, 0.604 was added mmoles) to a mixture of 1,1-dioxo-3,3-dibutyl-5- (4-chlorophenyl) -7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 99; 0.194 g, 0.402 mmol), anhydrous sodium carbonate (0.192 g, 1.81 mmol) and tetrabutylammonium bromide in MeCN (5 ml) The reaction mixture was heated at reflux for 3.5 hours. The solvent was evaporated under reduced pressure, and the residue was extracted with DCM / water. The organic layer was separated, dried and dried. evaporated under reduced pressure. The crude product was purified by column chromatography, using DCM / EtOAc (100: 5 and 100: 10) as the eluent, to give 0.197 g of the title compound (86%). NMR (300 MHz) 0.80-0.89 (m, 6H), 1.0-1.45 (m, 15H), 2.34 (s, 3H), 3.16 (s, 2H), 3.68 (s, 2H), 4.30 (q, 2H), 4.71 (s, 2H), 7.05-7.11 (m, 3H), 7.19 (s, 1H), 7.29-7.35 (m, 2H).

Method 101

1,1-Dioxo-3,3-dibutyl-5- (4-chlorophenyl) -7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

At a dissolution of 1,1-dioxo-3,3-dibutyl-5- (4-chlorophenyl) -7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 100; 0.195 g, 0.343 mmol) in ethanol (8 ml) NaOH was added (1.03 mmol in 0.5 ml of water). The reaction mixture was stirred at room temperature for 70 minutes, and then it was paralyzed by the addition of acetic acid (0.3 ml). The solvent is evaporated under reduced pressure, and the residue was extracted with DCM / water. The organic layer was separated, washed with brine, dried and dried. evaporated under reduced pressure to give the title compound 0.169 g (91%). NMR (500 MHz, CD 3 OD) 0.86 (t, 6H), 1.11-1.28 (m, 8H), 1.37-1.44 (m, 4H), 2.33 (s, 3H), 3.25 (s, 2H), 3.55 (s, 2H), 4.73 (s, 2H), 7.10-7.15 (m, 3H), 7.26 (s, 1H), 7.28-7.32 (m, 2H).

Method 102

1,1-Dioxo-3,3-dibutyl-5- (4-chlorophenyl) -7-methylthio-8- [ N - {(R) - α- [ N '- ( t -butoxycarbonylmethyl) carbamoyl] benzyl} -carbo-moylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 1,1-dioxo-3,3-dibutyl-5- (4-chlorophenyl) -7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 101 ; 100 mg, 0.185 mmol) and (R) -? - [ N - ( t -butoxycarbonylmethyl) carbamoyl} benzylamine (Method 86; 56 mg, 0.213 mmol) in DCM (4 mL) 2,6-lutidine ( 40 mg, 0.37 mmol) and TBTU (89 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then EtOAc was added, and the solution was washed with water. The organic layer was separated, dried and evaporated under reduced pressure. The crude product was purified by column chromatography, using DCM / MeOH (100: 3) as the eluent, to give 0.129 g of the title compound (89%). NMR (600 MHz) 0.78-82 (m, 6H), 1.01-1.23 (m, 8H), 1.30-1.42 (m, 13H), 2.32 (s, 3H) , 3.10-3.16 (m, 2H), 3.62-3.68 (m, 2H), 3.81-3.87 (m, 1H), 3.95-4.03 (m, 1H), 4.52 (dd, 2H), 5.57 (d, 1H), 6.27 (t, 1H), 7.01-7.07 (m, 3H), 7.20-7.43 (m, 8H), 8.02 (d, 1H).

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Method 103

3,3-Dibutyl-4-oxo-5- (4-nitrophenyl) -8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To 3,3-dibutyl-4-oxo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (synthesized by the procedure of W09616051 for the 3-butyl-3-ethyl analog corresponding; 2.9 g, 9.0 mmol) p-nitrophenyl bromide (24 g, 119 mmol), K 2 CO 3 (1.6 g, 12 mmol) and CuI (180 mg, 0.95 mmol). The reaction mixture was heated to 200 overnight. Then, it was allowed to cool to room temperature, and the resulting solid was purified by chromatography using DCM as the eluent. The fractions containing the product were concentrated under reduced pressure, EtOH (95%) was added, and the insoluble p-nitrophenyl bromide was then filtered off. The residue was purified again by flash chromatography, using DCM as eluent. The product was not yet pure, so that the residue was purified by flash chromatography using 1: 9 EtOAc: heptane as the eluent, to give 2.57 g of the title compound (64%). NMR (600 MHz) 0.77-0.87 (m, 6H), 1.12-1.31
(m, 8H), 1.4-1.6 (m, 4H), 3.09 (br s, 2H), 3.79 (s, 3H), 6.72-6.83 (m, 2H) , 7.18-7.27 (m, 3H), 8.3 (d, 2H).

Method 104

1,1-Dioxo-3,3-dibutyl-4-oxo-5- (4-nitrophenyl) -8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To 3,3-dibutyl-4-oxo-5- (4-nitrophenyl) -8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 103; 2.57 g, 5.8 mmol) DCM (130 ml), water (130) was added ml) and K 2 CO 3 (2.44 g, 17.6 mmol). Reaction mixture cooled to 0 ° C, and acid was added m-chloroperoxybenzoic acid (3.42 g, 13.9 mmol) in one single serving The reaction was allowed to complete overnight, the temperature rising slowly to room temperature. Then, aqueous (saturated) NaHCO3 was added, and the two layers were separated. The aqueous layer was then extracted three times with DCM. The Combined organic layers were dried, filtered and evaporated under reduced pressure. The product was purified by chromatography. ultrafast, using DCM as eluent, to give 2.4 g of title compound (87%). M / z 475.4.

Method 105

1,1-Dioxo-3,3-dibutyl-5- (4-aminophenyl) -8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To LiAlH4 (5.76 g, 151 mmol) was added tetrahydrofuran (200 ml). The reaction mixture was cooled to 0 ° C, and H 2 SO 4 (4.06 ml, 76 mmol) was added slowly with a syringe After the addition was finished, the reaction was stirred for 10 minutes. Then, the 1,1-dioxo-3,3-dibutyl-4-oxo-5- (4-nitrophenyl) -8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 104; 2.57 g, 5.06 mmol) at 0 ° C, dissolved in THF (50 ml). After stirring vigorously for 1 hour, the ice bath is removed, and the reaction was heated to 40 ° C overnight. Then I know added, in the following order, H 2 SO 4 {10} 2 O (3-4 tablespoons), water (8 ml), NaOH (15%, aqueous) (8 ml), water (25 ml) and MeOH (30 ml). The precipitate was removed by filtration, and rinsed with DCM / MeOH. The solvent was dried, dried filtered and concentrated under reduced pressure. The residue was purified by flash chromatography, using DCM: EtOAc, 9: 1 and then 3: 1, as eluent, to give 0.6 g of the title compound (27%). M / z 431.3.

Method 106

1,1-Dioxo-3,3-dibutyl-5- (4-aminophenyl) -8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

The 1,1-dioxo-3,3-dibutyl-5- (4-aminophenyl) -8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 105; 918 mg, 2.13 mmol) was dissolved in anhydrous DMF (20 ml) Sodium thiomethoxide (810 mg, 11.6 mmol) was added. The reaction mixture was treated at 100-120 ° C for four hours, and then at room temperature overnight. Be acetic acid (3 ml) was added, and the mixture was flooded with nitrogen (gaseous), and the gas was conducted through a flask that it contained sodium hypochlorite, in order to destroy the methylmercaptane formed. Water was added, and the aqueous layer was extracted twice with EtOAc. The combined organic layer was washed with brine, dried, filtered and evaporated under reduced pressure. The mixture contained DMF, so that toluene and brine were added (no everything dissolved). The aqueous layer was extracted twice with toluene. The combined organic layers were washed once with brine. He separating funnel was washed with EtOAc in order to dissolve everything. The toluene and EtOAc solutions were combined, dried, they were filtered and evaporated under reduced pressure. The residue is purified by flash chromatography, using DCM: EtOAc 7: 3 as eluent, to give 0.6 g of the title compound (27%). M / z 417.4.

Method 107

1,1-Dioxo-3,3-dibutyl-5- (4-t-butoxycarbonylaminophenyl) -8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

The 1,1-dioxo-3,3-dibutyl-5- (4-aminophenyl) -8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 106; 600 mg, 1.44 mmol) was dissolved in THF (10 ml). Be added di-t-butyl dicarbonate (314 mg, 1.44 mmol), and the mixture was stirred at 60 ° C for two hours, and at room temperature for 3 days. The solvent is evaporated under reduced pressure. EtOAc was added, and the organic layer was washed once with KHSO4 solution (0.3M, aqueous) and once with brine, dried, filtered and evaporated under reduced pressure. He residue was purified by flash chromatography, using DCM: EtOAc 9: 1 as eluent, to give 0.577 g of the compound of title (80%). M / z 517.3.

Method 108

1,1-Dioxo-3,3-dibutyl-5- (4-t-butoxycarbonylaminophenyl) -8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5- (4- t -butoxycarbonylamino-phenyl) -8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 107; 597 mg , 1.16 mmol) was dissolved in MeCN (20 ml), K 2 CO 3 (480 mg, 3.5 mmol), tetrabutylammonium bromide (54 mg, 0.17 mmol), and bromoacetate was added of ethyl (167 µL, 1.5 mmol). The mixture was heated at 60 overnight. The solvent was evaporated under reduced pressure. EtOAc and water were added, and the aqueous layer was extracted twice with EtOAc. The combined organic layer was washed once with brine, dried, filtered and evaporated under reduced pressure to give 0.617 g of the title compound (89%). M / z 603.3.

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Method 109

1,1-Dioxo-3,3-dibutyl-5- (4-t-butoxycarbonylaminophenyl) -8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5- (4- t -butoxycarbonylamino-phenyl) -8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 108; 607 mg , 1.0 mmol) was dissolved in THF (6 ml), water (6 ml) and LiOH (127 mg, 3.02 mmol, monohydrate) was added. The mixture was stirred for 1 hour. The mixture was poured into water, and the solution was acidified using a solution of HCl (aqueous, 1M). The aqueous layer was extracted twice with EtOAc. The combined organic layer was washed once with brine, dried, filtered and evaporated under reduced pressure to give 0.571 g of the title compound (99%). M / z 575.4.

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Method 110

1,1-Dioxo-3,3-dibutyl-5- (4-aminophenyl) -8- [ N - (α- (R) -methoxycarbonylbenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1, 5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5- (4- t -butyloxycarbonylamino-phenyl) -8- [ N - (α- (R) -methoxycarbonylbenzyl) carbamoylmethoxy] -2,3,4,5 -tetrahydro-1,5-benzothiazepine (Method 45; 562 mg, 0.78 mmol) was dissolved in DCM (18 ml). TFA (4 ml) was added, and the reaction mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure. The residue was partitioned between EtOAc and a solution of NaOH (1M, aqueous). The aqueous phase was extracted once more with EtOAc. The combined organic layer was washed with brine, dried, filtered and evaporated under reduced pressure to give 440 mg of the title compound (91%). M / z 622.5.

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Method 111

1,1-Dioxo-3,3-dibutyl-5- [4- ( N '- t -butylureido) phenyl] -8- [ N - (α- (R) -methoxycarbonylbenzyl) carbamoylmethoxy] -2,3, 4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5- (4-aminophenyl) -8- [ N - (α- (R) -methoxycarbonylbenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1 , 5-benzothiazepine (Method 110; 40 mg, 0.064 mmol) was dissolved in DMF (1 ml). T -butyl isocyanate (8.3 µL, 0.071 mmol) was added. The reaction mixture was stirred at 60-80 ° C overnight. Tert-Butyl isocyanate (20 µL, 0.171 mmol) was added. The reaction mixture was stirred at 60-80 ° C for 2 days, and then at room temperature for a few days. The solvent was evaporated under reduced pressure. The product was purified by preparative HPLC, using a gradient of MeCN / ammonium acetate buffer (5/95 to 100/0) as eluent, to give 30 mg of the title compound (65%). M / z 721.6.

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Method 112

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [ N - (? -Methoxycarbonylmethyl-benzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1, 5-benzothiazepine

The title compound was synthesized from the 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 17) and 3-amino-3-phenylpropanoate methyl (Helv. Chim. Acta; EN; 83; 6; 2000; 1256-1267) by the procedure of Example 56. M / z 639.4.

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Method 113

D- (S-trityl) t -butyl cysteinate hydrochloride

To a vigorously stirred suspension of S-trityl-D-cysteine (2.0 g, 5.5 mmol) in t -butyl acetate (35 ml) was added dropwise 70% HClO4 (1.6 ml) The reaction mixture was stirred at room temperature for 70 minutes, and EtOAc (50 ml) and NaHCO3 (aqueous, saturated) were added until pH 8.0. The precipitate, the unreacted S-trityl-D-cysteine, was filtered off. The organic layer was separated, washed with 0.5 M HCl (2 x 75 mL) and brine, dried and evaporated to give 2.02 g of the title compound (81%). NMR (500 MHz): 1.43 (s, 9H), 2.83-2.95 (m, 2H), 3.41-3.48 (m, 1H), 7.21-7.37 (m , 9H), 7.46 (d, 6H).

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Method 114

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonyl-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a suspension of the 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (Method 26; 12.85 g, 28.71 mmol) in MeCN (150 ml) was added ethyl bromoacetate (3.85 ml, 34.6 mmol), bromide tetrabutylammonium (0.925 g, 2.869 mmol) and sodium carbonate (12.85 g, 121.2 mmol). The mixture was heated at reflux for 5 hours. The solvent was removed under reduced pressure, and the residue was partitioned between DCM and 0.5 M HCl. The organic layer was washed with brine, dried (MgSO4) and concentrated. Chromatography using DCM / EtOAc (9: 1) as eluent gave 15.45 g of the product desired as a tan oil. NMR 0.70-0.85 (m, 6H), 1.00-1.55 (m, 15H), 2.15 (s, 3H), 3.10 (s, 2H), 3.70 (bs, 2H), 4.25 (q, 2H), 4.70 (s, 2H), 6.65 (s, 1H), 6.90-7.30 (m, 6H).

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Method 115

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-ethoxycarbonyl-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 116;
0.48 g, 1.04 mmol) was dissolved in ethanol (10 ml). NaOH (0.30 g, 7.5 mmol) was added, and the mixture was heated at reflux for 30 minutes. Acetic acid (1 ml) was added. The solvent was evaporated under reduced pressure, and the residue was extracted with DCM / water. The DCM layer was separated, dried and evaporated. 0.44 g (97%) of the title compound were obtained. NMR (300 MHz) 0.7-0.8 (m, 6H), 1.0-1.6 (m, 8H), 3.1-3.3 (m, 2H), 3.5-3, 8 (m, 2H), 4.6 (s, 3H), 6.8-7.3 (m, 7H), 7.5 (s, 1H).

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Method 116

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

The 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO9616051; 0.40 g, 1.07 mmol), ethyl bromoacetate (0.23 g, 1.38 mmol), sodium carbonate (0.50 g, 4.7 mmol) and tetrabutylammonium bromide (30 mg, 0.093 mmol) was added to MeCN (10 ml). The mixture was heated at reflux for 18 hours, and then evaporated under reduced pressure. The residue was extracted with DCM / water. The DCM layer was separated and evaporated under reduced pressure. The residue was purified by column chromatography. He product was eluted with DCM / EtOAc (90:10). 0.480 g were obtained (97%) of the title compound. NMR (300 MHz) 0.7-0.85 (m, 6H), 1.0-1.7 (m, 11H), 3.1-3.3 (m, 2H), 3.6-3.8 (m, 2H), 4.3 (q, 2H), 4.6 (s, 2H), 6.9-7.3 (m, 7H), 7.5 (d, 1 HOUR).

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Method 117

1,1-dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a suspension of the 1,1-dioxo-3,3-dipropyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine  (prepared in accordance with WO 96/16051 using identical synthetic stages, except that the starting material is chose to give the dipropyl compound instead of the compound of butyl / ethyl; 0.756 g, 1.62 mmol) in DMF (40 ml) NaSMe was added (0.605 g, 8.20 mmol, 95%), and the mixture was stirred overnight at 120 ° C. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and 0.5 M HCl. The aqueous layer was extracted two times more with EtOAc, and the combined organic extracts were dried (MgSO 4) and concentrated. The title compound was obtained. with a yield of 0.665 g (98%). NMR (500 MHz, DMSO-d 6) 0.60-0.80 (m, 6H), 1.05-1.50 (m, 8H), 2.15 (s, 3H), 3.20 (s, 2H), 3.65 (br s, 2H), 6.65 (s, 1H), 6.75-6.95 (m, 3H), 7.10-7.25 (m, 2H), 7.30 (s, 1H), 10.5 (s, 1H).

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Method 118

1,1-Dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a suspension of 1,1-dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine
(Method 117; 0.665 g, 1.58 mmol) in MeCN (10 ml) was added ethyl bromoacetate (0.262 ml, 2.35 mmol), tetrabutylammonium bromide (0.051 g, 0.158 mmol) and sodium carbonate (0.870 g , 8.21 mmol). The mixture was stirred overnight at 80 ° C. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and 0.5 M HCl. The organic layer was washed with brine, dried (MgSO 4) and concentrated. The residue was filtered through a short silica column (DCM: EtOAc-9: 1), concentrated and dissolved in EtOH (10 ml). A solution of NaOH (0.25 g, 6.25 mmol) in water (1 ml) was added, and the solution was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and 0.5 M HCl. The aqueous layer was extracted twice more with EtOAc, and the combined organic extracts were washed with brine and concentrated. The crude product was purified by preparative HPLC, using a gradient of MeCN / ammonium acetate buffer, to give the title compound with 0.441 g yield (58%) as a white solid. NMR (DMSO-d 6) 0.55-0.75 (m, 6H), 1.05-1.50 (m, 8H), 2.15 (s, 3H), 3.20 (s, 2H), 3.65 (br s, 2H), 4.50 (s, 2H), 6.65 (s, 1H), 6.80-7.00 (m, 3H), 7.15 (s, 1H), 7.15-7.25 (m, 2H).

Example 121

The following illustrates representative forms of pharmaceutical dosage containing the compound of formula (I), or a pharmaceutically acceptable salt, a solvate, a solvate of such salt or a prodrug thereof (hereinafter "compound X "), for therapeutic or prophylactic use in humans:

(to) Compressed I mg / tablet Compound X 100 Lactose Ph. Eur 182.75 Croscarmellose sodium 12.0 Starch paste corn (5% pasta p / v) 2.25 Stearate magnesium 3.0

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(b) Compressed II mg / tablet Compound X fifty Lactose Ph. Eur 223.75 Croscarmellose sodium 6.0 Starch corn 15.0 Polyvinylpyrrolidone (5% w / v paste) 2.25 Stearate magnesium 3.0

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(C) Compressed III mg / tablet Compound X 1.0 Lactose Ph. Eur 93.25 Croscarmellose sodium 4.0 Starch paste corn (5% pasta p / v) 0.75 Stearate magnesium 1.0

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(d) Capsule mg / capsule Compound X 10 Lactose Ph. Eur. 488.5 Magnesium 1.5

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(and) Injection I (fifty mg / ml) Compound X 5.0% p / v 1M hydroxide solution sodium 15.0% v / v Hydrochloric acid 0.1 M (to adjust the pH to 7.6) Polyethylene Glycol 400 4.5% p / v Water for injection until 100%

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(F) Injection II (10 mg / ml) Compound X 1.0% p / v BP sodium phosphate 3.6% p / v 0.1 M hydroxide solution sodium 15.0% v / v Water for injection up 100%

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(g) Injection III (1 mg / ml, pH buffered 6) Compound X 0.1% p / v BP sodium phosphate 2.26% p / v Citric acid 0.38% p / v Polyethylene Glycol 400 3.5% p / v Water for injection until 100%

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Note

The above formulations can be obtained by conventional procedures well known in the art Pharmaceutical The tablets (a) - (c) can be provided with enteric coating by conventional means, for example for provide an acetate-phthalate coating of cellulose.

Claims (47)

1. A compound of formula (I): 87 in the that: R v and R w are selected, independently of hydrogen or alkyl C 1-6; R 1 and R 2 are selected, independently, from C 1-6 alkyl;

quad

R X and R Y are selected, independently of hydrogen or alkyl C 1-6, or one of R X and R Y is hydrogen or C 1-6 alkyl and the other is hydroxy or alkoxy C 1-6;

quad

R z is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyl -oxy, N - (C 1-6 alkyl) amino, N, N - (C 1-6 alkyl ) 2-amino, C 1-6 alkanoyl-amino, N - (C 1-6 alkyl) -carbamoyl, N, N- (C 1-6 alkyl) 2 carbamoyl , C 1-6 alkyl-S (O) a in which a is 0 to 2, C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonylamino, ureido, N ' - (C 1-6 alkyl) ureido, N - (C 1-6 alkyl) ureido, N ', N - (C 1-6 alkyl) 2 ureido, N ' - (alkyl C 1-6) - N - (C 1-6 alkyl) ureido, N ', N' - (C 1-6 alkyl) 2 - N - (C 1-6 alkyl ) ureido, N - (C 1-6 alkyl) sulfamoyl and N, N - (C 1-6 alkyl) 2 sulfamoyl;

v is 0-5; one of R 4 and R 5 is a group of formula (IA): 88

quad

R 3 and R 6 and the other of R 4 and R 5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, C 2-4 achenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyl - oxy, N - (C 1-4 alkyl) amino, N, N - (C 1-4 alkyl) 2 amino, C 1-4 alkanoyl -amino, N- (C_ alkyl 1-4) carbamoyl, N, N - (C 1-4 alkyl) 2 carbamoyl, C 1-4 alkyl -S (O) a in which a is 0 to 2 , C 1-4 alkoxycarbonyl, N - (C 1-4 alkyl) sulfamoyl and N, N - (C 1-4 alkyl) 2 sulfamoyl; wherein R 3 and R 6 and the other of R 4 and R 5 may be optionally substituted on the carbon with one or more R 16;

D is -O-, -N (R a) -, -S (O) b - or -CH (R a) -; in which R a is hydrogen or C 1-6 alkyl, and b is 0-2;

quad

ring A is aryl or heteroaryl; in which the ring A is optionally substituted with one or more substituents selected from R17;

quad

R 7 is hydrogen, alkyl C 1-4, carbocyclyl or heterocyclyl; in which R 7 is optionally substituted with one or more substituents selected from R18;

R 8 is hydrogen or alkyl C 1-4; R 9 is hydrogen or alkyl C 1-4;

quad

R 10 is hydrogen, alkyl C 1-4, carbocyclyl or heterocyclyl; in which R 10 is optionally substituted with one or more substituents selected from R19;

quad

R 11 is carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P (O) (OR c) (OR d), -P (O) (OH) (OR c), -P (O) (OH) (R d) or -P (O) (OR c) (R d), in which R c and R d are independently selected from alkyl C 1-6; or R 11 is a group of formula (IB):

89 in the that: X is -N (R q) -, -N (R q) C (O) -, -O-, and -S (O) a -; where a is 0-2 and R q is hydrogen or C 1-4 alkyl; R 12 is hydrogen or alkyl C 1-4;

quad

R 13 and R 14 are selected, independently, of hydrogen, C 1-4 alkyl, carbocyclyl, heterocyclyl or R23; in which said alkyl C 1-4, carbocyclyl or heterocyclyl may be optionally substituted, independently, with one or more substituents selected from R20;

quad

R 15 is carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P (O) (OR e) (OR f), -P (O) (OH) (OR e), -P (O) (OH) (R e) or -P (O) (OR e) (R f), in which R e and R f are independently select from alkyl C 1-6; or R 15 is a group of formula (IC):

90 in the that: R 24 is selected from hydrogen or alkyl C 1-4;

quad

R 25 is selected from hydrogen, alkyl C 1-4, carbocyclyl, heterocyclyl or R 27; wherein said C 1-4 alkyl, carbocyclyl or heterocyclyl may be optionally substituted, so independent, with one or more substituents selected from R 28;

quad

R 26 is selected from carboxy, sulfo, sulfine, phosphono, tetrazolyl, -P (O) (OR g) (OR h), -P (O) (OH) (OR g), -P (O) (OH) (R g) or -P (O) (OR g) (R h), in which R g and R h are independently select from alkyl C 1-6;

p is 1-3; in which the values of R 13 may be the same or different; q is 0-1; r is 0-3; in which the values of R 14 may be the same or different; m is 0-2; in which the values of R 10 may be the same or different; n is 1-3; in which the values of R 7 may be the same or different; z is 0-3; in which the values of R 25 may be the same or different;

quad

R 16, R 17 and R 18 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, alkenyl C 2-4, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyl -oxy, N - (C 1-4 alkyl }) amino, N, N - (C 1-4 alkyl) 2 amino, C 1-4 alkanoyl -amino, N- (C 1-4 alkyl) carbamoyl, N, N - (C 1-4 alkyl) 2 carbarnoyl, C 1-4 alkyl -S (O) a in which a is 0 to 2, C 1-4 alkoxycarbonyl, N - (C 1-4 alkyl) sulfamoyl and N, N - (C 1-4 alkyl) 2 sulfamoyl; wherein R 16, R 17 and R 18 may be optionally independently substituted on the carbon with one or more R 21;

quad

R 19, R 20, R 23, R 27 and R 28 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto , sulfamoyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyl -oxy, N - (C 1-4 alkyl) amino, N, N - (C 1-4 alkyl) 2-amino, C 1-4 alkanoyl -amino, N - (alkyl C 1-4) carbamoyl, N, N - (C 1-4 alkyl) 2 carbamoyl, C 1-4 alkyl -S (O) a in which a is 0 a 2, C 1-4 alkoxycarbonyl, N - (C 1-4 alkyl) -sulfamoyl, N, N - (C 1-4 alkyl) 2 sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P (O) (OR a) (OR b), -P (O) (OH) (OR a), -P (O) ( OH) (R a) or -P (O) (OR a) (R b), in which R a and R b are independently selected from C 1-6 alkyl; wherein R 19, R 20, R 23, R 27 and R 28 may be optionally independently substituted on the carbon with one or more R 22;

quad

R21 and R22 are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy , vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N- methylcarbamoyl, N, N- dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N- methyl sulfamoyl and N, N- dimethyl ;

quad

or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof,

in which heteroaryl is a mono- or ring bicyclic, totally unsaturated, containing 3-12 atoms, of which at least one atom is chosen from nitrogen, sulfur or oxygen, which may, unless otherwise specified mode, be linked by carbon or nitrogen; in which aryl is a mono- or carbon ring bicyclic, totally unsaturated, containing 3-12 atoms; in which heterocyclyl is a mono- or ring bicyclic, saturated, partially saturated or unsaturated, which it contains 3-12 atoms, of which at least one atom is chosen from nitrogen, sulfur or oxygen, which can, except otherwise specified, be linked by carbon or by nitrogen; Y in which carbocyclyl is a carbon ring mono- or bicyclic, saturated, partially saturated or unsaturated, which It contains 3-12 atoms. 2. A compound of formula (I) according to claim 1, wherein R v and R w are both hydrogen, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an ester or an amide in vivo hydrolysable thereof. 3. A compound of formula (I) according to one of claims 1 or 2, wherein R1 and R2 are independently selected from ethyl, propyl or butyl, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof. 4. A compound of formula (I) according to any one of claims 1 to 3, wherein R x and R y are both hydrogen, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an ester or an in vivo hydrolysable amide thereof. 5. A compound of formula (I) according to any one of claims 1 to 4, wherein R z is selected from halo, amino, C 1-6 alkyl, C 1-6 alkoxy - carbonylamino or N '- (C 1-6 alkyl) ureido, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an ester or an in vivo hydrolysable amide thereof. 6. A compound of formula (I) according to any one of claims 1 to 5, wherein v is 0 or 1, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolyzable ester or amide of the same. 7. A compound of formula (I) according to any one of claims 1 to 6, wherein R3 is hydrogen, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an ester or hydrolysable amide in I live from it. A compound of formula (I) according to any one of claims 1 to 7, wherein R 4 and R 5 which is not the group of formula (IA) is selected from hydrogen, halo, C 1-4 alkoxy or C 1-4 alkyl -S (O) a, wherein a is 0 to 2; wherein R 4 or R 5 may be optionally substituted on the carbon with one or more R 16; wherein R 16 is independently selected from hydroxy, carboxy and N, N - (C 1-4 alkyl) 2-amino, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof. 9. A compound of formula (I) according to any one of claims 1 to 8, wherein R5 is a group of formula (IA) (as depicted in claim 1), and R4 } is methylthio, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof. 10. A compound of formula (I) according to any one of claims 1 to 9, wherein R6 is hydrogen, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an ester or hydrolysable amide in I live from it. 11. A compound of formula (I) according to a any one of claims 1 to 10, wherein in the group of formula (IA): D is -O- or -S-;

quad

Ring A is phenyl, thienyl or indolyl; in which ring A is optionally substituted with one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl;

R 7 is hydrogen, methyl or phenyl; R 8 is hydrogen or methyl; R 9 is hydrogen or methyl; R 10 is hydrogen; m is 0-2, in which the values of R 10 may be the same or different; Y

quad

R 11 is carboxy, -P (O) (OH) (OEt), or a group of formula (IB) (as represented in claim 1); or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof.

12. A compound of formula (I) according to a any one of claims 1 to 11, wherein in the group of formula (IB): R 12 is hydrogen or methyl;

quad

R 13 is hydrogen, methyl, ethyl, butyl or phenyl or R 23; wherein R 13 is optionally substituted with one or more substituents selected from R20; R 20 is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto; in which R 20 may be optionally substituted on carbon with one or more hydroxy; R 23 is carboxy;

X is -NH- or -NHC (O) -;

quad

R 14 is selected from hydrogen, methyl or phenyl; wherein said methyl or phenyl may optionally be substituted with one or more substituents selected from hydroxy;

quad

R 15 is carboxy, sulfo, phosphono, -P (O) (OR e) (OR f), -P (O) (OH) (OR e), -P (O) (OH) (R e) or -P (O) (OR e) (R f), in the that R e and R f are independently selected from methyl or ethyl, or R 15 is a group of formula (IC) (as represented in claim 1);

p is 1-3, in which the values of R 13 may be the same or different; q is 0-1; Y r is 0-3, in which the values of R 14 may be the same or different; or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof. 13. A compound of formula (I) according to a any one of claims 1 to 12, wherein in the group of formula (IC): R 24 is hydrogen; R 25 is hydrogen; R 26 is carboxy; Y z is 1; or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof.

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14. A compound of formula (I) according to the claim 1, wherein: R v and R w are both hydrogen; R 1 and R 2 are selected, independently, from C 1-4 alkyl; R X and R Y are both hydrogen; R z is selected from halo, amino, C 1-6 alkyl, C 1-6 alkoxycarbonylamino or N '- (C 1-6 alkyl) ureido; v is 0 or 1; R 3 and R 6 are hydrogen;

quad

one of R 4 and R 5 is a group of formula (IA) (as represented in claim 1) and the other is selected from hydrogen, halo, C 1-4 alkoxy or C_ alkyl {1-4 -S (O) a in which a is 0 to 2; wherein R 4 or R 5 may be optionally substituted on the carbon with one or more R 16; wherein R 16 is independently selected from hydroxy, carboxy and N, N - (C 1-4 alkyl) 2 amino;

D is -O- or -S-; R 7 is hydrogen, methyl or phenyl; R 8 is hydrogen or methyl;

quad

ring A is aryl or heteroaryl; in which the ring A is optionally substituted with one or more substituents selected from R17; wherein R 17 is selected from halo, hydroxy, C 1-4 alkyl or alkoxy C 1-4; in which R 17 may be optionally substituted on carbon with one or more R 21; in which R 21 is selected from halo;

R 9 is hydrogen or methyl; R 10 is hydrogen;

quad

R 11 is carboxy, -P (O) (OH) (OR c) in which R c is selected from C 1-4 alkyl, or a group of formula (IB) (as represented in the claim one);

R 12 is hydrogen or methyl; X is NH- or -NHC (O) -;

quad

R 13 is hydrogen, alkyl C 1-4, carbocyclyl or R 23; in which R 13 is optionally substituted with one or more substituents selected from R20; wherein R 20 is hydroxy, alkyl C 1-4 -S (O) a where a is 0, C 1-4 alkoxy, amino, carbocyclyl, heterocyclyl or mercapto; in which R 20 can be optionally independently substituted on carbon with one or more R22; R22 is selected from hydroxy; Y R 23 is carboxy;

quad

R 14 is selected from hydrogen, alkyl C 1-4 or carbocyclyl; in which said alkyl C_ {1-4} or carbocyclyl may optionally be substituted with one or more substituents selected from R20; Y R 20 is hydroxy;

quad

R 15 is carboxy, sulfo, phosphono, -P (O) (OR e) (OR f), -P (O) (OH) (OR e), -P (O) (OH) (R e) or -P (O) (OR e) (R f), in the that R e and R f are independently selected from alkyl C 1-4, or R 15 is a group of formula (IC) (as depicted in claim 1);

R 24 is hydrogen; R 25 is hydrogen; R 26 is carboxy; p is 1-3; in which the values of R 13 may be the same or different; q is 0-1; r is 0-3; in which the values of R 14 may be the same or different; m is 0-2; in which the values of R 10 may be the same or different; n is 1-2; in which the values of R 7 may be the same or different; z is 0-1; in which the values of R 25 may be the same or different; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an ester or an in vivo hydrolysable amide thereof. 15. A compound of formula (I) according to the claim 1, selected from: 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [ N ' - (carboxymethyl) carbamoyl] methyl} - carbamoilme-
toxi) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [ N '- (carboxymethyl) carbamoyl] -4-hydroxybenzyl} -carbamoyl-
methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [ N ' - (2-sulfoethyl) carbamoyl] methyl } -carbamoylmeth-
xi) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl-1 '- [ N ' - (2-sulfoethyl) carbamoyl ] methyl} -carbamoylme-
toxi) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [ N '- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl} - carbamoilme-
toxi) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) - α- [ N '- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl } -carbamoil-
methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [ N '- (2-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,
3,4,5-tetrahydro-1,5-banzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [ N '- (2-carboxyethyl) carbamoyl] -4-hydroxybenzyl} - carbamoil-
methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) - α- [ N '- (5-carboxypentyl) carbamoyl] benzyl} -carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [ N '- (2-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2 ,3,
4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {α- [ N '- (2-sulfoethyl) carbamoyl] -2-fluorobenzyl} -carbamoylmethoxy) -2 ,
3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {(R) - α- [ N '- (R) - (2-hydroxy-1- carboxyethyl) carbamoyl] benzyl} -carba-
moylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [ N '- (R) - (2-hydroxy-1-carboxyethyl) carbamoyl] benzyl} -carba-
moylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- { N - [(R) -? - ( N '- {(R) -1- [ N ''- ( R) - (2-hydroxy-1-carboxyethyl) carbamoyl] -2-
hydroxyethyl} carbamoyl) benzyl] carbamoylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {α- [ N '- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4 , 5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- ( N - {α- [ N '- ((ethoxy) (methyl) phosphorylmethyl) carbanoyl] benzyl} -carbamoyl -
methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- { N - [(R) - α- ( N '- {2 - [(hydroxy) (methyl) phosphoryl ] ethyl} carbamoyl) -benzyl] -
carbamoylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R)} -? - [ N '- (2-methylthio-1-carboxyethyl) carbamoyl] benzyl } -carbamoil-
methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- { N - [(R) -? - ( N '- {2 - [(methyl) (ethyl) phosphoryl] ethyl } carbamoyl) -4-hydroxybenzyl] -carbamoylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- { N - [(R) -? - ( N '- {2 - [(methyl) (hydroxy) phosphoryl] ethyl } carbamoyl) -4-hydroxy-
benzyl] carbamoylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -? - [(R) - N '- (2-methylsulfinyl-1-carboxyethyl) carbamoyl] -benzyl} -
carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; Y 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8- [ N - {(R) -? - [ N '- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl} - carbamoylmeth-
xi] -2,3,4,5-tetrahydro-1,5-benzothiazepine; or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof. 16. A procedure for the preparation of a compound of formula (I) according to any one of the claims 1 to 15, comprising: Procedure 1): oxidize a Benzothiazepine of formula (II): 91 Procedure 2): for compounds of formula (I) wherein D is -O-, -NRa or -S-, react a compound of formula (IIIa) or (IIIb): 92 with a compound of formula (IV): 93 in which L is a group scrollable;

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Procedure 3): react an acid of formula (Va) or (Vb):

         \ vskip1.000000 \ baselineskip
      

94 or an activated derivative thereof, with an amine of formula (SAW):

         \ vskip1.000000 \ baselineskip
      

95 Procedure 4): for compounds of formula (I) in which R 11 is a group of formula (IB), to react a compound of formula (I), wherein R 11 is carboxy, with a amine of formula (VII):

         \ vskip1.000000 \ baselineskip
      

96 Procedure 5): for compounds of formula (I) wherein R 11 is carboxy, deprotect a compound of formula (VIIIa):

         \ vskip1.000000 \ baselineskip
      

97

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or (VIIIb): 98 in which R P is alkyl C 1-4; Procedure 6): for compounds of formula (I) wherein R 11 is a group of formula (IB), and R 15 is carboxy, deprotect a compound of formula (IXa): 99 or (IXb): 100 in which R P is alkyl C 1-4;

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Procedure 7) for compounds of formula (I) in which one of R 4 and R 5 is selected, independently of alkyl C_ {1-4} -thio optionally substituted on carbon with one or more R 16, react a compound of formula (Xa) or (Xb):

         \ vskip1.000000 \ baselineskip
      

101 in which L is a group movable, with a thiol of formula (XI): (XI) R y -H wherein R y is alkyl C_ {1-4} -thio optionally substituted on carbon with one or more R 16; Procedure 8) for compounds of formula (I) in which R 15 is a group of formula (IC), to react a compound of formula (IXa) or (IXb), wherein R P is hydrogen, with a compound of formula (XII):

         \ vskip1.000000 \ baselineskip
      

102 Procedure 9): for compounds of formula (I) wherein R 11 is a group of formula (IB), and R 15 is a group of formula (IC) and R 26 is carboxy, deprotect a compound of formula (XIIIa):

         \ vskip1.000000 \ baselineskip
      

103

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or (XIIIb):

         \ vskip1.000000 \ baselineskip
      

104

         \ vskip1.000000 \ baselineskip
      

and R P is alkyl C 1-4; Procedure 10): for compounds of formula (I) in which X is -N (R q) C (O) -, do reacting a compound of formula (XIVa):

         \ vskip1.000000 \ baselineskip
      

105

         \ vskip1.000000 \ baselineskip
      

or (XIVb):

         \ vskip1.000000 \ baselineskip
      

106

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with a compound of formula (XV): 107 and then, if necessary or desirable:

i)

convert a compound of the formula (I) in another compound of the formula (I);

ii)

delete any of the groups protectors;

iii)

forming a pharmaceutically acceptable salt, solvate, solvate of such salt or an ester or a hydrolysable amide in vivo .

17. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, for use as a medicament. 18. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, for use in a method of prophylactic or therapeutic treatment of a warm-blooded animal, such as man. 19. The use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, in the manufacture of a medicament for use in the production of an IBAT inhibitory effect on a warm-blooded animal, such as man. 20. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, in association with a pharmaceutically acceptable diluent or carrier. 21. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, and an HMG CoA reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, in association with a pharmaceutically acceptable diluent or carrier. 22. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, and a bile acid binder, in association with a pharmaceutically acceptable diluent or carrier. 23. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, and an HMG CoA reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, and a bile acid binder, in association with a pharmaceutically acceptable diluent or carrier. 24. A composition, combination or use according to any one of claims 21, 23, 34, 36, 37 or 39 wherein the HMG CoA reductase inhibitor is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof. 25. A composition, combination or use according to a any of claims 21, 23, 34, 36, 37 or 39, in the that the HMG CoA reductase inhibitor is rosuvastatin, or a pharmaceutically acceptable salt of the same. 26. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, and an agonist of PPAR alpha and / or gamma, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

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27. A composition, combination or use, according to any one of claims 26, 46 or 47, wherein the PPAR alpha and / or gamma agonist is acidic (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid, or a pharmaceutically acceptable salt thereof. 28. A compound of formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) or (XIIIb), (as represented in claim 16), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an ester or an in vivo hydrolysable amide thereof. 29. A compound of formula (IXb) according to claim 28, which is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ( N - {(R) -1'-phenyl -1 '- [ N ' - ( t -butoxycarbonylmethyl) -carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine. 30. The use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, in the manufacture of a medicament for use in the treatment of hyperlipidemic states in a warm-blooded animal, such as man. 31. The use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, in the manufacture of a medicament for use in the treatment of dyslipidemic conditions and disorders such as hyperlipidemia, hypertriglyceridemia, hyperbetalipoproteinemia (elevated LDL), hyperprebetalipoproteinemia (elevated VLDL), hyperquilomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (HDL in an animal Hot blood, just like man. 32. The use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, in the manufacture of a medicament for use in the treatment of different pathological conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hypertrombotic states, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart disease, cardiovascular diseases, myocardial infarction, angina pectoris, peripheral venous insufficiencies , inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurysms, stenosis, restenosis, vascular plaques, vascular fat stretch marks, leukocyte infiltration, monocytes and / or macrophages, intimal thickening, thinning of the media , infectious and surgical trauma and vascular thrombosis, stroke and ischemic attacks tr anxious, in a warm-blooded animal, such as man. 33. The use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, in the manufacture of a medicament for use in the treatment of atherosclerosis, coronary heart disease, myocardial infarction, angina pectoris, peripheral venous insufficiencies, stroke and transient ischemic attacks, in a warm-blooded animal, such as man. 34. A combination, comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, a HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof. 35. A combination, comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, and a bile acid binder. 36. A combination, comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, and a bile acid binder. 37. The use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, an inhibitor of HMG Co-A reductase, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, in the manufacture of a medicament for use in the treatment of hyperlipidemic states in a blood animal Hot, just like man. 38. The use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, and a binder of bile acids, in the manufacture of a medicament for use in the treatment of hyperlipidemic states in a warm-blooded animal, such as man. 39. The use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, an inhibitor of HMG Co-A reductase, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, and a bile acid binder, in the manufacture of a medicament for use in the treatment of hyperlipidemic states in a warm-blooded animal, such as man. 40. A composition, combination or use according to a any of claims 22, 23, 35, 36, 38 and 39, in the that the bile acid binder is a resin. 41. A composition, combination or use according to a any of claims 22, 23, 35, 36, 38 and 39, in the that the bile acid binder is cholestyramine or colestipol 42. A combination for use as a medicament comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, optionally together with a pharmaceutically acceptable carrier or diluent, with a cholesterol absorption antagonist, for simultaneous, sequential or separate administration. 43. A combination according to claim 42, in which the cholesterol absorption antagonist is azetidinone 44. A combination according to claim 42 or claim 43, wherein the absorption antagonist of the Cholesterol is SCH 58235. 45. A composition, combination or use according to any one of claims 21, 23, 34, 36, 37 or 39, wherein the HMG Co-A reductase inhibitor is fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin, mevastatin and rosuvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, or a pharmaceutically acceptable salt thereof. 46. A combination comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, according to any one of claims 1 to 15, and a PPAR alpha and / or gamma agonist, or a pharmaceutically acceptable salt thereof. 47. The use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, and an alpha and / or gamma PPAR agonist, or a pharmaceutically acceptable salt, solvate, solvate of such salt or an in vivo hydrolysable ester or amide thereof, in the manufacture of a medicament for use in the treatment of hyperlipidemic states in a warm-blooded animal, such as man.